HIV inhibiting N-aminoimidazole derivatives

ABSTRACT

An N-aminoimidazole or N-aminoimidazolethione derivative, a pharmaceutically acceptable salt, a tautomer, an isomer, an ester or glycosylation product thereof, said derivative being represented by general formula (I): wherein m=zero or 1, n=zero or 1, R 1  is selected from hydrogen, methyl or ethyl, R 2  is selected from hydrogen, SH or —SR 0  wherein R 0  is methyl, benzyl or glucose residue; Q is selected from 1-naphtyl, 2-naphtyl, biphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, thienyl, or a substituted or unsubstituted phenyl ring, wherein the substitution is understood as being one or two substituents selected from H, F, Cl, Br, I, methyl, ethyl or isopropyl; L is selected from 1-naphtyl, 2-naphtyl, biphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, thienyl, or a substituted or unsubstituted phenyl ring wherein the substitution is understood as being one or two substituents selected from H, F, Cl, Br, I, methyl, ethyl or isopropyl. This invention further relates to the use of compounds of formula (I) as agents having biological activity, especially against viral infections.

The present invention relates to discovery of new N-aminoimidazole andN-aminoimidazole-thione derivatives. The invention further relates tocompounds having HIV (Human Immunodeficiency Virus) replicationinhibiting properties. The present invention also relates to compoundshaving antiviral activities with respect to other viruses, as well ascompounds having antitumoral properties. The invention also relates tomethods for preparation of all such compounds and pharmaceuticalcompositions comprising them. The invention further relates to the useof said compounds in the manufacture of a medicament useful for thetreatment of subjects suffering from HIV infection, as well as fortreatment of other viral, retroviral or lentiviral infections, treatmentof animals suffering from FIV, viral, retroviral, lentiviral infectionsor treatment of tumour cells.

BACKGROUND OF THE INVENTION

It is well documented that the ability of HIV to rapidly evolve drugresistance, together with toxicity problems requires the development ofadditional classes of antiviral drugs: AICA-riboside [a) P. D. Cook, R.K. Robins, J. Am. Chem. Soc. 1976, 78, 1492; b) A. Yamazaki, M. Okutsu,J. Heteroclycl. Chem. 1978, 15, 3353; c) T. Kalman, D.Houston,Nucleosides & Nucleotides 1989, 8, 899; d) M. Wall, S. J. Benkovic,J.Med.Chem., 1999, 42, 3421](1-(-D-ribofuranosyl)-5-amino-4-imidazolecarboxamide) is an example ofan open ring purine nucleoside showing potent antiviral activity. EICAR[A. Matsuda, T. Sasaki, T. Ueda, Chem. Pharm. Bull. 1988, 36, 2730](5-alkynyl-1-D-ribof u ranosylimidazole-4-carboxamide), likewise animidazole derivative, shows a strong antileukemia activity. Also abicyclic imidazole containing non-nucleoside derivative [E. J. Saloski,Tetrahedron Lett. 1995, 36, 1387] is reported as a HIV-1 reversetranscriptase inhibitor.

Many non nucleoside derivatives have been reported to inhibitproliferation of HIV and especially non-nucleoside reverse transcriptaseinhibitors (NNRTI) make up a large part of these compounds. Excellentreviews describing these NNRTI can be found [a) M. Witvrouw et al.,AIDS, 1999, 13, 1477–1483; b) E. De Clercq, Il Farmaco 1999, 54, 26–45].A few N-aminoimidazolethione derivatives have been reported before andwere obtained by a multistep reaction from α-halo-ketones, potassiumthiocyanate and monosubstituted hydrazines [J. G. Schantl, I. M. Lagoja,Heterocycles, 1997, 45, 691].

However, there is still a need for compounds which either complementexisting drugs such that the resulting cocktail has improved resistanceto virus mutation or compounds which are themselves effective againstmany or all viable mutations of a virus.

SUMMARY OF THE INVENTION

The present invention relates to N-aminoimidazole andN-aminoimidazole-thione derivatives. The invention further relates tocompounds having HIV (Human Immunodeficiency Virus) replicationinhibiting properties. The present invention also relates to compoundshaving antiviral activities with respect to other viruses, as well ascompounds having antitumoral properties. The invention also relates tomethods for preparation of all such compounds and pharmaceuticalcompositions comprising them. The invention further relates to the useof said compounds in the manufacture of a medicament useful for thetreatment of subjects suffering from HIV infection, as well as fortreatment of other viral, retroviral or lentiviral infections, treatmentof animals suffering from FIV, viral, retroviral, lentiviral infectionsor treatment of tumour or cancer cells.

One aspect of the present invention is the provision of N-aminoimidazoleand N-aminoimidazolethione derivatives, compounds of formula (I) whicheffectively show antiviral properties, in particular against HumanImmunodefiency Virus (HIV), which is the etiological agent of AcquiredImmune Deficiency Syndrome (AIDS) in humans, and consequently may beuseful for the treatment of individuals infected by HIV.

The present invention relates to the use of compounds of formula (I),pharmaceutically acceptable salts, tautomers, isomers, esters andglycosylation products thereof, wherein:

-   m is 1 or more preferably zero;-   n is zero or 1;-   R¹ is selected from hydrogen, methyl or ethyl;-   R² is selected from hydrogen and —SH;-   Q is selected from 1-naphtyl, 2-naphtyl, biphenyl, 2-pyridyl,    3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl,    thienyl, carboxyl, aminocarbonyl, alkylamino-carbonyl,    dialkylaminocarbonyl, phenylaminocarbonyl, alkyloxycarbonyl or    phenyl;    -   wherein alkyl is a methyl, ethyl, propyl or isopropyl and phenyl        is a substituted or unsubstituted phenyl ring represented by the        general formula (II)

wherein o is 1 or 2, and R³ is selected from H, F, Cl, Br, I, hydroxy,alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, carboxyl,aminocarbonyl, alkylaminocarbonyl, alkyloxycarbonyl, methyl, ethyl,propyl, isopropyl or C₁₋₃ haloalkyl wherein haloalkyl contains 1 to 4haloatoms and alkyl is selected from methyl, ethyl, propyl or isopropyl;and L is selected from 1-naphtyl, 2-naphtyl, biphenyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pynmidyl, 5-pyrimidyl, thienyl, ora substituted or unsubstituted phenyl ring represented by the generalformula (III)

wherein p is 1 or 2, and R⁴ is selected from H, F, Cl, Br, I, hydroxy,alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, carboxyl,aminocarbonyl, alkylaminocarbonyl, alkyloxycarbonyl, methyl, ethyl,propyl, isopropyl or C₁₋₃ haloalkyl wherein haloakyl contains 1 to 4haloatoms and alkyl is selected from methyl, ethyl, propyl or isopropyl,for the manufacture of a medicine or as a pharmaceutically activeingredient, especially as a virus replication inhibitor, preferably aretrovirus replication inhibitor or a non-nucleoside drug, for instancefor the manufacture of a medicament or pharmaceutical composition havingantiviral activity for the prevention and/or treatment of viral,preferably retroviral, infections in humans and mammals. The presentinvention further relates to a method of treatment of tumor or cancercells in a mammal, including a human, comprising administering to themammal in need of such treatment an effective amount of a compound offormula (I) as an active ingredient in admixture with at least apharmaceutically acceptable carrier The present invention furtherrelates to a method of treatment of a viral infection, preferably aretroviral infection in a mammal, including a human, comprisingadministering to the mammal in need of such treatment a therapeuticallyeffective amount of a compound of formula (I) as an active ingredient,preferably in admixture with at least a pharmaceutically acceptablecarrier.

The present invention also relates to compounds of formula (I) per se,their pharmaceutically acceptable salts, tautomers, isomers, esters andglycosylation products, with the further proviso that the said compound(I) is not selected from

-   -   1-(3-Chlorophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;    -   1-(2-Chlorophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;    -   1-(4-Chlorophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;    -   1-(phenylamino)-2,3-Dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;    -   1-(4-nitrophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;    -   1-(4-methylphenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;    -   1-(4-methyloxyphenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;    -   1-(benzylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;    -   4-Methyl-5-phenyl-1-phenylamino-1H-imidazole;    -   4-Methyl-5-phenyl-1-(4-nitrophenyl)amino-1H-imidazole;    -   4-Methyl-5-phenyl-1-(4-chlorophenyl)amino-1H-imidazole;    -   4-Methyl-5-phenyl-1-(4-methylphenyl)amino-1H-imidazole; or    -   4-Methyl-5-phenyl-1-(4-methyloxyphenyl)amino-1H-imidazole.

The compounds of formula (I) will be designated as N-aminoimidazolederivatives when R² is hydrogen, and as N-aminoimidazolethionederivatives when R² is —SH. Reason for adopting the latter designationis because when R² is —SH, the thione functional group represented informula (9) of FIG. 2 below is the readily available and wellcharacterized tautomer of the —SH thiol group via a hydrogen shift from4-C to 3-N.

The invention further relates to methods for the preparation ofcompounds of formula (I), to pharmaceutical compositions comprising themin admixture with at least a pharmaceutically acceptable carrier, theactive ingredient preferably being in a concentration range of about0.1–100% by weight, and to the use of these derivatives namely asnon-nucleoside drugs useful for the treatment of subjects suffering fromHIV infection.

The invention further relates to the use of a composition comprising:

(a) one or more derivatives of formula (I), and

(b) one or more retroviral enzyme inhibitors

as biologically active agents in respective proportions such as toprovide a synergistic effect against a viral infection, preferably alentiviral infection and more preferably a retroviral infection in amammal, for instance in the form of a combined preparation forsimultaneous, separate or sequential use in retroviral infectiontherapy. Within the framework of this embodiment of the invention, theretroviral enzyme inhibitors used as a therapeutically activeingredients (b) may belong to categories already known in the art andinclude, among others:

-   -   HIV integrase inhibitors such as are well known in the art,    -   reverse transcriptase inhibitors such as for instance        delavirdine, dideoxyadenosine, foscarnet sodium, stavudine,        suramin sodium, zalcitabine and the like,    -   Nucleoside reverse transcriptase inhibitors such as for instance        zidovudine, lamivudine, didanosine and the like,    -   Non-nucleoside reverse transcriptase inhibitors such as for        instance nevirapine and the like,    -   HIV protease inhibitors such as for instance saquinavir,        ritonavir, indinavir, nelfinavir and the like.

When using a combined preparation of (a) and (b):

-   -   the active ingredients (a) and (b) may be administered to the        mammal (including a human) to be treated by any means well known        in the art, i.e. orally, intranasally, subcutaneously,        intramuscularly, intradermally, intravenously, intra-arterially,        parenterally or by catheterization.    -   the therapeutically effective amount of the combined preparation        of (a) and (b), especially for the treatment of viral infections        in humans and other mammals, preferably is a retroviral enzyme        inhibiting amount. More preferably, it is a retroviral        replication inhibiting amount of derivative (a) and a retroviral        enzyme inhibiting amount of inhibitor (b). Still more preferably        when the said retroviral enzyme inhibitor (b) is a protease        inhibitor, its effective amount is a protease inhibiting amount.        When the said retroviral enzyme inhibitor (b) is a reverse        transcriptase inhibitor, its effective amount is a reverse        transcriptase inhibiting amount. When the said retroviral enzyme        inhibitor (b) is an integrase inhibitor, its effective amount is        an integrase inhibiting amount.    -   ingredients (a) and (b) may be administered simultaneously but        it is also beneficial to administer them separately or        sequentially, for instance within a relatively short period of        time (e.g. within about 24 hours) in order to achieve their        functional fusion in the body to be treated.

The invention also relates to the compounds of formula (I) being usedfor inhibition of the proliferation of other viruses than HIV,preferably the inhibition of viral activity of hepatitis B virus,hepatitis C virus or flaviviruses, with in particular yellow fever virusor Dengue virus.

The invention further relates to the compounds of formula (I) being ableto reduce the proliferation of cells, especially tumour or cancer cells.

More generally, the invention relates to the compounds of formula (I)being useful as agents having biological activity (preferably antiviralor antitumoral activity) or as diagnostic agents. Any of the usesmentioned with respect to the present invention may be restricted to anon-medical use, a non-therapeutic use, a non-diagnostic use, orexclusively an in vitro use, or a use related to cells remote from ananimal.

The term “pharmaceutically acceptable salts” as used herein means thetherapeutically active non-toxic acid addition salt forms which thecompounds of formula (I) are able to form and which may conveniently beobtained by treating the base form of such compounds with an appropriateacid. Examples of such appropriate acids include, for instance,inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike; or organic acids such as, for example, acetic, propanoic,hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, lactic, pyruvic,oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid),maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic (i.e. 2-hydroxybenzoic), p-aminosalicylic and the like. Thisterm also includes the solvates which the compounds of formula (I) aswell as their salts are able to form, such as for example hydrates,alcoholates and the like.

The term “isomers” as used herein means all possible isomeric forms,including tautomeric forms, which the compounds of formula (I) maypossess. Unless otherwise stated, the chemical designation of compoundsdenotes the mixture of all possible stereochemically isomeric forms,said mixtures containing all diastereomers and enantiomers (since thecompounds of formula (1) may have at least one chiral center) of thebasic molecular structure. More particularly, stereogenic centers mayhave either the R- or S-configuration, and substituents may have eithercis- or trans-configuration.

Pure isomeric forms of the said compounds are defined as isomerssubstantially free of other enantiomeric or diastereomeric forms of thesame basic molecular structure. In particular, the term“stereoisomerically pure” or “chirally pure” relates to compounds havinga stereoisomeric excess of at least about 80% (i.e. at least 90% of oneisomer and at most 10% of the other possible isomers), preferably atleast 90%, more preferably at least 94% and most preferably at least97%. The terms “enantiomerically pure” and “diastereomerically pure”should be understood in a similar way, having regard to the enantiomericexcess, respectively the diastereomeric excess, of the mixture inquestion.

Consequently, if a mixture of enantiomers is obtained during any of thefollowing preparation methods, it can be separated by liquidchromatography using a suitable chiral stationary phase. Suitable chiralstationary phases are, for example, polysaccharides, in particularcellulose or amylose derivatives. Commercially available polysaccharidebased chiral stationary phases are ChiralCel™ CA, OA, OB, OC, OD, OF,OG, OJ and OK, and Chiralpak™ AD, AS, OP(+) and OT(+). Appropriateeluents or mobile phases for use in combination with said polysaccharidechiral stationary phases are hexane and the like, modified with analcohol such as ethanol, isopropanol and the like.

The terms cis and trans are used herein in accordance with ChemicalAbstracts nomenclature and refer to the position of the substituents ona ring moiety. The absolute stereochemical configuration of thecompounds of formula (I) may easily be determined by those skilled inthe art while using well-known methods such as, for example, X-raydiffraction.

The term “pharmaceutically acceptable carrier” as used herein means anymaterial or substance with which the active ingredient is formulated inorder to facilitate its application or dissemination to the locus to betreated, for instance by dissolving, dispersing or diffusing the saidcomposition, and/or to facilitate its storage, transport or handlingwithout impairing its effectiveness. The pharmaceutically acceptablecarrier may be a solid or a liquid or a gas which has been compressed toform a liquid, i.e. the compositions of this invention can suitably beused as concentrates, emulsions, solutions, granulates, dusts, sprays,aerosols, suspensions, ointments, creams, tablets, pellets or powders.

Suitable pharmaceutical carriers for use in the said pharmaceuticalcompositions and their formulation are well known to those skilled inthe art, and there is no particular restriction to their selectionwithin the present invention. They may also include additives such aswetting agents, dispersing agents, stickers, adhesives, emulsifyingagents, solvents, coatings, antibacterial and antifungal agents (forexample phenol, sorbic acid, chlorobutanol), isotonic agents (such assugars or sodium chloride) and the like, provided the same areconsistent with pharmaceutical practice, i.e. carriers and additiveswhich do not create permanent damage to mammals. The pharmaceuticalcompositions of the present invention may be prepared in any knownmanner, for instance by homogeneously mixing, coating and/or grindingthe active ingredients, in a one-step or multi-steps procedure, with theselected carrier material and, where appropriate, the other additivessuch as surface-active agents. may also be prepared by micronisation,for instance in view to obtain them in the form of microspheres usuallyhaving a diameter of about 1 to 10 μm, namely for the manufacture ofmicrocapsules for controlled or sustained release of the activeingredients.

Suitable surface-active agents to be used in the pharmaceuticalcompositions of the present invention are non-ionic, cationic and/oranionic materials having good emulsifying, dispersing and/or wettingproperties. Suitable anionic surfactants include both water-solublesoaps and water-soluble synthetic surface-active agents. Suitable soapsare alkaline or alkaline-earth metal salts, unsubstituted or substitutedammonium salts of higher fatty acids (C₁₀–C₂₂), e.g. the sodium orpotassium salts of oleic or stearic acid, or of natural fatty acidmixtures obtainable form coconut oil or tallow oil. Syntheticsurfactants include sodium or calcium salts of polyacrylic acids; fattysulphonates and sulphates; sulphonated benzimidazole derivatives andalkylarylsulphonates. Fatty sulphonates or sulphates are usually in theform of alkaline or alkaline-earth metal salts, unsubstituted ammoniumsalts or ammonium salts substituted with an alkyl or acyl radical havingfrom 8 to 22 carbon atoms, e.g. the sodium or calcium salt oflignosulphonic acid or dodecylsulphonic acid or a mixture of fattyalcohol sulphates obtained from natural fatty acids, alkaline oralkaline-earth metal salts of sulphuric or sulphonic acid esters (suchas sodium lauryl sulphate) and sulphonic acids of fatty alcohol/ethyleneoxide adducts. Suitable sulphonated benzimidazole derivatives preferablycontain 8 to 22 carbon atoms. Examples of alkylarylsulphonates are thesodium, calcium or alcanolamine salts of dodecylbenzene sulphonic acidor dibutyl-naphtalenesulphonic acid or a naphtalene-sulphonicacid/formaldehyde condensation product. Also suitable are thecorresponding phosphates, e.g. salts of phosphoric acid ester and anadduct of p-nonylphenol with ethylene and/or propylene oxide, orphospholipids. Suitable phospholipids for this purpose are the natural(originating from animal or plant cells) or synthetic phospholipids ofthe cephalin or lecithin type such as e.g. phosphatidylethanolamine,phosphatidylserine, phosphatidylglycerine, lysolecithin, cardiolipin,dioctanylphosphatidyl-choline, dipalmitoylphoshatidyl-choline and theirmixtures.

Suitable non-ionic surfactants include polyethoxylated andpolypropoxylated derivatives of alkylphenols, fatty alcohols, fattyacids, aliphatic amines or amides containing at least 12 carbon atoms inthe molecule, alkylarenesulphonates and dialkylsulphosuccinates, such aspolyglycol ether derivatives of aliphatic and cycloaliphatic alcohols,saturated and unsaturated fatty acids and alkylphenols, said derivativespreferably containing 3 to 10 glycol ether groups and 8 to 20 carbonatoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms inthe alkyl moiety of the alkylphenol. Further suitable non-ionicsurfactants are water-soluble adducts of polyethylene oxide withpoylypropylene glycol, ethylenediaminopolypropylene glycol containing 1to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250ethyleneglycol ether groups and/or 10 to 100 propyleneglycol ethergroups. Such compounds usually contain from 1 to 5 ethyleneglycol unitsper propyleneglycol unit. Representative examples of non-ionicsurfactants are nonylphenol-polyethoxyethanol, castor oil polyglycolicethers, polypropylene/polyethylene oxide adducts,tributylphenoxypolyethoxyethanol, polyethyleneglycol andoctylphenoxypolyethoxyethanol. Fatty acid esters of polyethylenesorbitan (such as polyoxyethylene sorbitan trioleate), glycerol,sorbitan, sucrose and pentaerythritol are also suitable non-ionicsurfactants.

Suitable cationic surfactants include quaternary ammonium salts,preferably halides, having 4 hydrocarbon radicals optionally substitutedwith halo, phenyl, substituted phenyl or hydroxy; for instancequaternary ammonium salts containing as N-substituent at least oneC₈-C₂₂ alkyl radical (e.g. cetyl, lauryl, palmityl, myristyl, oleyl andthe like) and, as further substituents, unsubstituted or halogenatedlower alkyl, benzyl and/or hydroxy-lower alkyl radicals.

A more detailed description of surface-active agents suitable for thispurpose may be found for instance in “McCutcheon's Detergents andEmulsifiers Annual” (MC Publishing Crop., Ridgewood, N.J., 1981),“Tensid-Taschenbuch”, 2^(nd) ed. (Hanser Verlag, Vienna, 1981) and“Encyclopaedia of Surfactants (Chemical Publishing Co., New York, 1981).

Additional ingredients may be included in order to control the durationof action of the active ingredient in the composition. Control releasecompositions may thus be achieved by selecting appropriate polymercarriers such as for example polyesters, polyamino acids, polyvinylpyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose,carboxymethylcellulose, protamine sulfate and the like. The rate of drugrelease and duration of action may also be controlled by incorporatingthe active ingredient into particles, e.g. microcapsules, of a polymericsubstance such as hydrogels, polylactic acid, hydroxymethylcellulose,polymethyl methacrylate and the other above-described polymers. Suchmethods include colloid drug delivery systems like liposomes,microspheres, microemulsions, nanoparticles, nanocapsules and so on.Depending on the route of administration, the pharmaceutical compositionmay require protective coatings.

Pharmaceutical forms suitable for injectionable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation thereof. Typical carriers for this purposetherefore include biocompatible aqueous buffers, ethanol, glycerol,propylene glycol, polyethylene glycol and the like and mixtures thereof.

In view of the fact that, when several active ingredients are used incombination, they do not necessarily bring out their joint therapeuticeffect directly at the same time in the mammal to be treated, thecorresponding composition may also be in the form of a medical kit orpackage containing the two ingredients in separate but adjacent form. Inthe latter context, each active ingredient may therefore be formulatedin a way suitable for an administration route different from that of theother ingredient, e.g. one of them may be in the form of an oral orparenteral formulation whereas the other is in the form of an ampoulefor intravenous injection or an aerosol.

The compounds of formula (I) can be prepared while using a series ofchemical reactions well known to those skilled in the art, altogethermaking up the process for preparing said compounds and exemplifiedfurther. The processes described further are only meant as examples andby no means are meant to limit the scope of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows scheme 1: General synthetic procedure for preparingrespectively the starting bromoketones (2) and the hydrazine derivatives(4) for use with embodiments of the present invention, wherein R⁶ is—(CH₂)_(n)-Q, R⁵ is —(CH₂)_(m)-L and R¹, L, Q, m and n are as defined informula (I).

FIG. 2 shows scheme 2: General synthetic procedure for preparing therespective N-aminoimidazole-2-thiones (9) for use with embodiments ofthe present invention.

FIG. 3 shows scheme 3: General synthetic procedure for reducing therespective N-aminoimidazole-2-thiones (9) into N-aminoimidazolederivatives (13) for use with embodiments of the present invention.

FIG. 4 shows scheme 4: General synthetic procedure for alkylating therespective N-aminoimidazole-2-thiones (9) into S-alkyl-N-aminoimidazolederivatives (14) for use with embodiments of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Materials and Preparation Methods

Most starting materials are commercially available (e.g. from ACROS,Aldrich, Fluka). Commercially not available ketones (1) can be obtainedvia Grignard reaction of the corresponding nitrites through procedureswell known in the art. The α-halo-ketones (2) can be synthesized bybromination of ketones (1) with bromine in dichloromethane. Usingdiazotation followed by reduction, hydrazines (4) can be obtained fromthe corresponding primary amines. The synthetic strategies are shown inscheme 1 of FIG. 1.

The compounds of formula (I) with R²═SH, can be prepared by firstreacting a α-haloketone (2) with an alkali thiocyanate such as potassiumthiocyanate to obtain a thiocyanatoketone (3); the obtainedthiocyanatoketone can be further reacted with a hydrazine derivative (4)into the hydrazone, which spontaneously will rearrange into the1-amino-2-imidazolethione derivative (9) (compounds of formula (I) withR²═SH). The corresponding synthetic strategies are shown in scheme 2 ofFIG. 2. Compounds of formula (I) with R²═H, can be obtained bydesulfurizing the former obtained 1-amino-2-imidazolethione derivativeswith e.g. hydrogen peroxide to obtain the 1-amino-imidazole derivativesof formula (I) with R²═H (13). The corresponding synthetic strategy isshown in scheme 3 of FIG. 3.

Alternatively, the compounds of formula (I) with R²═SH (9) can beobtained in a one pot procedure as outlined below.

Hereto, the α-halo-ketone (2) and alkali thiocyanate such as potassiumthiocyanate can be first reacted in acetic acid, after which themonosubstituted hydrazine (4) is added to the resulting mixture atambient temperature. For some combinations of reactants mild heating canbe required to obtain the 1-amino-2-imidazolethione derivative (9) whichcan be isolated using standard procedures. The corresponding syntheticstrategy is shown in scheme 2 of FIG. 2. Examples of compounds offormula (I) with R²═SH obtained by this method are shown in table 1.Both alternatives may be summarized as a process for preparing acompound of formula (I), a pharmaceutically acceptable salt, a tautomer,an isomer, an ester or a glycosylation product thereof, comprising thesteps of reacting an α-haloketone having the formulaQ-(CH₂)_(n)—CO—CHR₁X, wherein Q, R₁ and n are as defined in formula (I)and X is a halogen atom, first with an alkali thiocyanate and then witha hydrazine derivative having the formula L-(CH₂)_(m)—NHNH₂, therebyobtaining an N-aminoimidazolethione derivative having the formula (I)wherein R₂ is —SH.

Prior research has been done to gain insight into the mechanism of thisreaction. As already reported [J. G. Schantl, I. M. Lagoja,Heterocycles, 1997, 45, 691. ], this multistep reaction is considered tofollow the path outlined in scheme 2 of FIG. 2. In a first step theα-halo-ketone (2) is reacted with an alkali thiocyanate such aspotassium thiocyanate to obtain the thiocyanatoketone (3), which isconverted by reaction with hydrazine (4) into the hydrazone (5). Thishydrazone (5) easily can undergo a 1,4-elimination forming thecorresponding azoalkene [J. G. Schantl, M. Prean, Monatsh. Chem. 1993,124, 299. ] (6) and thiocyanic acid. These intermediates subsequentlyundergo a [3+2] cycloaddition reaction [J. G. Schantl, H. P. Kählig, M.Prean, Heterocycles, 1994, 37, 1873. ]. The azo-alkene (6) is serving asan isoelectronic hetero-allyl anion equivalent whereas the thiocyanicacid reacts as dipolarophile. The resulting heterocyclic azomethineimine intermediate (7) is anticipated to equilibrate with the zwitterion(8) by a proton transfer from the thiourea NH to the more basicexocyclic nitrogen atom. The 1-amino-2,3-dihydro-1H-imidazole-2-thione(9) is provided from a final 1,2-hydrogen shift from 4-C to 3-N.

The 1-amino-1H-imidazole derivatives (13) or compounds of formula (I)with R²═H can be obtained with an oxidative reduction of the substituted1-amino-2,3-dihydro-1H-imidazole-2-thiones (9) as shown in scheme 3 ofFIG. 3. Examples of the imidazoles (13) derived by this method arereported in table 2. Desulfurization of thioureas has been achieved inthe past by using Raney nickel [C. Temple, J. Med. Chem. 1990, 33, 656.], nitric acid [J. Davoll, J. Chem. Soc. 1958, 1593. ], singlet oxygen[W. M. Abdou, M. M. Sidky, H. Wamhoff, Z. Naturforsch., B. 1987, 42,1153. ], ozone [C. Crestini, E. Mincione, R. Saladino, R. Nicoletti,Tetrahedron, 1994, 50, 3259. ], ferric chloride [M. M. Fraser, R. A.Raphael, J. Chem. Soc. 1952, 226. ] or hydrogen peroxide [a) H. -J.Schönherr, H. -W. Wanzlick, Chem. Ber, 1970, 103, 1037; b) D. W.Karkhanis, L. Field, Phosphorus Sulfur, 1985, 22, 49; c) S. Grivas, E.Ronne, Acta Chem. Scand. 1995, 49, 225; d) J. G. Schantl, I. M. Lagoja,Heterocycles, 1998, 48, 929.].

A suitable procedure consists of treating a compound of formula (I)wherein R²═SH (9) with 30% hydrogen peroxide at 10° C., selectivelycleaving off the sulfur atom of the 2-thione function. As reported inprior art, hereby at first oxidation of the sulfur atom can take place(scheme 3, FIG. 3). Upon loss of SO_(n) from the sulfonic acidintermediate (10) or possibly from the zwitterionic isomer (11), theresultant carbene-type intermediate (12) can undergo a proton shift toyield the 1-amino-1H-imidazole derivative (13).

Alkylation of 1-amino-2-imidazolethione derivative compounds 9 by meansof an alkylating agent having the formula R⁰X, wherein R⁰ is e.g. methylor benzyl, can quantitatively yield the S-alkyl derivatives (14). Thereaction is shown in scheme 4 of FIG. 4. Under Mitsunobu conditions [D.L. Comins, G. Jianhua, Tetrahedron Lett. 1994, 35, 2819–2822. ] theS-alkyl-derivatives can also be obtained. Only in case of glycosylationby means of a glycosylating agent under Verbrueggen conditions, atemperature dependent S- or N-glycoslyation product can be formed [I. M.Lagoja, A. Van Aerschot, C. Hendrix, P. Herdewijn, Collect. Czech. Chem.Commun. 2000, 65, 1145–1155].

The following examples are provided for the purpose of illustrating thepresent invention and should in no way be interpreted as limiting thescope thereof.

EXAMPLES A. General Methods

NMR spectra were recorded on a Varian, Gemini 200 spectrometer (¹H-200MHz, ¹³C 50 MHz). All NH protons were assigned by exchange with D₂O. Incase of AA′BB′ systems determination of J is based on the assumption ofan AB quartett [E. D. Becker in: “High Resolution NMR, Theory andChemical Application”, Academic Press, New York, 1969, 169. ] Exact massmeasurements were performed on a quadrupole—time of flight massspectrometer (Q-Tof-2, Micromass, Manchester, UK) equipped with astandard electrospray ionization (ESI) interface. Samples were infusedin a 2-propanol: water (1:1) mixture at 3 mL/min. TLC was performed withTLC aluminum sheets (Merck, Silica gel 60 F₂₅₄) and silica (200–425mesh) was used for column chromatography. Melting points (mp [° C.])were determined with a Kofler-Bank.

All starting materials are commercially available (e.g. from ACROS,Aldrich, Fluka) or can be obtained as outlined further.

B. Intermediate Compounds B.1. SYNTHESIS OF KETONES (1) FROM NITRILESVIA GRIGNARD REACTION: GENERAL PROCEDURE

In a 2-neck flask equipped with a reflux condenser and a dropping funnela suspension of magnesium (2.83 g, 0.12 mol) and alkylbromide (0.12 mol)in dry ether were stirred under nitrogen. After addition of a crystal ofiodine the reaction started. After the reaction was completed a solutionof the nitrile (0.1 mol) in dry ether (15 mL) was added dropwise.Following heating under reflux for 6 hours the mixture was quenched with6N H₂SO₄ ice (100 mL). To complete the hydrolysis of the ketimine themixture was warmed and afterwards extracted with ether. After removingthe solvent the resulting ketones could be used without furtherpurification.

Isobutylphenylketone (1.01)

[Evans, Gordon, J. Chem. Soc. 1938, 1434, 1438. ] Yield: quant; ¹H-NMR(CDCl₃): 0.97, 1.00 (6H, 2×s, 2×CH₃), 2.29 (1 H, m, CH), 2.80 (2H, d,J=6.6 Hz, CH₂), 7.43–7.63 (3H, m, 3,4,5H Ar), 7.93 (2H, (d), 2,6H Ar).

Butyrophenone (1.02)

[H. Gilman, J. Eitsch, J. Am. Chem. Soc. 1957, 79, 2150–2153. ] Yield:quant; ¹H-NMR: 0.98 (3H, t, J=7.4 Hz, CH₃), 1.74 (2H, t×q, J=7.4 Hz,CH₂), 2.91 (2H, t, J=7.4 Hz, CH₂CO), 7.37–7.58 (3H, m, 3,4,5H Ar), 7.92(2H, (d), 2,6H Ar).

Ethyl-2-thiophenylketone (1.03)

Yield: quant; ¹H-NMR: 1.89 (3H, t, J=7 Hz, CH₃), 2.89 (2H, q, J=7 Hz,CH₂), 7.09 (1H, m, 4-H), 7.53–7.70 (2H, m, 3,5-H).

B.2. SYNTHESIS OF 3-CYANOPROPIOPHENONE

[H. R. Sonaware, N. S. Bellur, D. G.

Based on Kulkarni, N. R. Ayyangar, Tetrahedron, 1994, 50, 1243–1260. ]:A mixture of 3-bromopropiophenone (10.65 g, 50 mmol), CuCN (5.82 g, 65mmol) in DMF (35 mL) was heated under reflux for 6 h. After cooling themixture to ambient temperature FeCl₃ (5 g) in H₂O (30 mL)/HCl conc (10mL) was added and heated to 80° C. for another 20 min. After cooling toroom temperature and extraction with ether further purification occurredby destination under reduced pressure (bp.: 140° C., 10 torr). Theketone could be obtained as slightly yellow, low melting (42° C.) solid.

3-Cyanopropiophenone (1.06)

Yield: 81%, ¹H-NMR (CDCl₃): 1.29 (3H, t, J=7.2 Hz, CH₃), 3.11 (2H, q,J=7.2 Hz, CH₂), 7.69 (1H, (t), J˜8 Hz, 5-H Ar), 7.90 (1H, d, J=7.6 Hz,4-H Ar), 8.24 (1H, d, J=8.2 Hz, 6-H Ar), 8.29 (1H, s, 2-H Ar).

B.3. SYNTHESIS OF 3-METHOXYCARBONYLPROPRIOPHENONE

After refluxing 3-cyanopropiophenone 1.06 (3.5 g) with KOH (2.5 g) inethanol (30 mL) for 2 hours the nitrile could be hydrolyzed to thecorresponding acid derivative. Following removal of the solvent,dilution of the alkaline residue with water and acidification, the acidcould be isolated, which was converted into the ester 1.07 by treatmentwith methanol (20 mL) and H₂SO₄ conc. (1 mL). After removing the solventthe residue was diluted with water and extracted with ethyl acetate.After drying the organic layer over Na₂SO₄ and removing the solvent the3-methoxycarbonylpropiophenone 1.07 could be isolated in 85% yield over2 steps.

3-Methoxycarbonylpropiophenone (1.07)

Yield: 85%, ¹H-NMR (CDCl₃): 1.23 (3H, t, J=7.2 Hz, CH₃), 3.06 (2H, q,J=7.2 Hz, CH₂), 3.95 (3H, s, CH₃O), 7.58 (1H, (t), J˜8 Hz, 5-H Ar),8.20–8.27 (2H, m, 4,6-H Ar), 8.60 (1H, s, 2-H Ar).

B.4. SYNTHESIS OF α-HALO-kETONES: GENERAL PROCEDURE

To an ice-cooled solution of the corresponding ketone 1 (0.04 mol),bromine (0.04 mol, 2 mL) was added dropwise. The almost colorlesssolution was stirred at room temperature for another 20 min. Afteraddition of aqueous NaHCO₃-solution (100 mL) the organic layer wasseparated and dried over Na₂SO₄. Following removal of the solvent theketones could be used without further purification. In case of3-cyanopropiophenone 1.06 in contrast the reaction needed to be heatedunder reflux.

α-Bromopropiophenone (2.01)

[N. De Kimpe, R. Verhe, L. De Buyck, N. Schamp, J. Org. Chem. 1980, 45,2803–2813.1] Yield: quant; ¹H-NMR (CDCl₃): 1.90 (3H, d, J=6.6 Hz, CH₃),5.31 (1H, d, J=6.6 Hz, CH), 7.42–7.58 (3H, m, 3,4,5 H Ar), 8.00 (2H,(d), 2,6 H Ar).

α-Bromo-3′-bromopropiophenone (2.02)

[N. De Kimpe, R. Verhe, L. De Buyck, N. Schamp, Tetrahedron Lett., 1980,21, 2257–2260.]_Yield: quant; ¹H-NMR (CDCl₃): 1.90 (3H, d, J=6.6 Hz,CH₃), 5.24 (1H, q, J=6.6 Hz, CH), 7.34 (1H, (t), J˜7.8 Hz, 5-H Ar), 7.69(1H, d, J=7.6 Hz, 4-H Ar), 7.92 (1H, d, J=7.8 Hz, 6-H Ar), 8.12 (1H, s,2-H Ar).

α-Bromo-4′-bromopropiophenone (2.03)

[K. L. Nelson J. C. Robertson, J. J. Duvall J. Am. Chem. Soc. 1964, 86,684–687. ] Yield: quant; ¹H-NMR (CDCl₃): 1.90 (3H, d, J=6.6 Hz, CH₃),5.24 (1H, q, J=6.6 Hz, CH), 7.55, 7.60 (2H, 2,6H Ar)-7.83, 7.87 (2H,3,5H Ar, AA′BB′ J˜8.2 Hz).

α-Bromo-3′chloropropiophenone (2.04)

[L. Szotyory, E. Hamburg, J. Prakt. Chem. 1963, 22, 202–213. ] Yield:quant; ¹H-NMR (CDCl₃): 1.89 (3H, d, J=6.6 Hz, CH₃), 5.25 (1H, q, J=6.6Hz, CH), 7.41 (1H, (t), J˜7.8 Hz, 5-H Ar), 7.55 (1H, d, J=7.6 Hz, 4-HAr), 7.89 (1H, d, J=7.8 Hz, 6-H Ar), 7.96 (1H, s, 2-H Ar).

α-Bromo-4′-chloropropiophenone (2.05)

[B. L. Chenard, J. Bordner, T. W. Butler, L. K. Chambers, M. A. Collins,J. Med. Chem. 1995, 38, 3138–3145. ] Yield: quant; ¹H-NMR (CDCl₃): 1.91(3H, d, J=6.6 Hz, CH₃), 5.25 (1H, q, J=6.6 Hz, CH), 7.43, 7.48 (2H, 2,6HAr)-7.94, 7.99 (2H, 3,5H Ar, AA′BB′ J˜8.4 Hz).

α-Bromo-4′methoxypropiophenone (2.06)

[C. W. Perry M. V. Kalnins, K. H. Deitcher J. Org. Chem. 1972, 37,4371–4376. ] Yield: quant; ¹H-NMR (CDCl₃): 1.88 (3H, d, J=6.6 Hz, CH₃),3.84 (3H, s, CH₃O), 5.27 (1H, q, J=6.6 Hz, CH), 6.90, 6.95 (2H, 2,6HAr)-7.96, 8.01 (2H, 3,5H Ar, AA′BB′ J˜8.2 Hz).

α-Bromophenylacetone (2.07)

[A. v. Wacek, K. Kratzl, A. v. Bezard, Chem. Ber. 1942, 75, 1348, 1352.] Yield: quant; ¹H-NMR (CDCl₃): 2.27 (3H, s, CH₃), 5.44 (1H, s, CH),7.33–7.46 (5H, m, Ar).

α-Bromobutyrophenone (2.08)

[N. De Kimpe, R. Verhe, L. De Buyck, N. Schamp, Tetrahedron Lett., 1980,21, 2257–2260. ] Yield: quant; ¹H-NMR (CDCl₃): 1.08 (3H, t, J=7.4 Hz,CH₃), 2.18 (2H, q×d, J¹=6.6 Hz, J²=7.4 Hz CH₂), 5.08 (1H, t, J=6.6 Hz),7.47–7.62 (3H, m, 3,4,5H Ar), 8.02 (2H, (d), 2,6 H Ar).

α-Bromoisobutylphenylketone (2.09)

[E. G. Boswell, D. L. Musso, J. L. Kelley, F. E. Soroko, B. R. Cooper,J. Heterocycl. Chem. 1996, 33, 33–40. ] Yield: quant; ¹H-NMR (CDCl₃):1.05, 1.23 (6 H, 2×d, J=6.6 Hz, 2×CH₃), 2.47 (1H, m, CH), 5.01 (1H, d,J=8.4 Hz, CHC═O), 7.41–7.66 (5H, m, Ar).

α-Bromoacetylacetone (2.10)

[E. Bienvenue-Goetz, J. -E. Dubois, J. Am. Chem. Soc. 1981, 103,5388–5392.]_Yield: quant; ¹H-NMR (CDCl₃): 2.36 (3H, s, CH₃), 3.75 (3H,s, CH₃O), 4.77 (1H, s, CH).

α-Bromo-2-ketobutyricacidmethylester (2.11)

[W. S. Lee, K. D. Nam, H. -G. Hahn, H. D. Mah, J. Heterocycl. Chem.,1993, 30, 1105, 1110. ] Yield: quant; ¹H-NMR (CDCl₃): 1.78 (3H, d, J=6.6Hz, CH₃), 3.88 (3H, s, CH₃O), 5.15 (1H, q, J=6.6 Hz

α-Bromo-3′cyanopropiophenone (2.12)

[L. Villa et. al. Farmaco Ed. Sci. 1974, 29, 73–79. ] Yield: quant;¹H-NMR (CDCl₃): 1.94 (3H, d, J=6.4 Hz, CH₃), 5.30 (1H, q, J=6.4 Hz, CH),7.66 (1H, (t), J˜7.8 Hz, 5-H Ar), 7.90 (1H, d, J=6.6 Hz, 4-H Ar), 8.25(1H, d, J=8 Hz, 6-H Ar), 8.31 (1H, s, 2-H Ar).

α-Bromo-3′methoxycarbonylpropiophenone (2.12)

Yield: quant; ¹H-NMR (CDCl₃): 1.94 (3H, d, J=6.6 Hz, CH₃), 3.96 (3H, s,CH₃O), 5.31 (2H, q, J=6.6 Hz, CH₂), 7.62 (1H, (t), J˜8 Hz, 5-H Ar),8.20–8.28 (2H, m, 4,6-H Ar), 8.66 (1H, s, 2-H Ar).

α-Bromo-thiophenylethylketone (2.12)

Yield: quant; ¹H-NMR (CDCl₃): 1.86 (2H, d, J=6.4 Hz, CH₃), 5.18 (1H, q,J=6.4 Hz, CH), 7.12 (1H, t, J=6 Hz, 4-H), 7.69 (1H, d, J=6 Hz, 3-H),7.81 (1H, d, J=6 Hz, 5-H).

B.5. SYNTHESES OF N-MONOSUBTITUTED HYDRAZINES FROM ANILINES: GENERALPROCEDURE

A suspension of the corresponding aniline (0.082 mol) was cooled to −10°C. A solution of NaNO₂ (5.7 g, 0.09 mol) in water (10 mL) was slowlyadded keeping the temperature always beyond −5° C. The red solutionformed was stirred at −10° C. for another 30 min, after which a solutionof SnCl₂ (47 g, 0.25 mol) in HCl_(conc). (50 mL) was slowly added. Awhite precipitate was immediately formed. After the addition wascompleted the mixture was stored at 4° C. overnight and followingfiltration and washing with hexane the precipitate was suspended in 10%NaOH (200 mL). After extraction with ether, drying over Na₂SO₄ andremoving the solvent, the obtained hydrazine could be used withoutfurther purification.

3,5-Dimethylphenylhydrazine (4.01)

[Borsche, Groth, Just. Lieb. Ann. Chem. 1941, 238–247. ] Yield: 72%;¹H-NMR (DMSO-d₆): 2.17 (6H, s, 2 CH₃), 3.90 (2H, s, br ex, NH₂), 6.25(1H, s, 4-H Ar), 6.42 (2H, s, 2,6-H Ar), 6.65 (1H, s, br, ex, NH).

3-Methoxyphenylhydrazine (4.02)

[Kermack, Perkin, Robinson, J. Chem. Soc. 1921, 119, 1641. ] Yield: 74%;3.67 (3H, s, CH₃O),), 3.90 (2H, s, br ex, NH₂), 6.13 (1H, d, J=8 Hz, 6-HAr), 6.32–6.40 (2H, m, 2-H Ar, 4-H Ar), 6.63 (1H, s, br ex, NH), 6.97(1H, (t), J=8 Hz, 5-H Ar).

B.6. SYNTHESIS OF 1-AMINO-2,3-DIHYDRO-1H-IMIDAZOLE-2-THIONES: GENERALPROCEDURE

[J. G. Schantl, I. M. Lagoja, Heterocycles, 1997, 45, 691.]:

To a stirred solution of the α-halo ketone 2 (2.5 mmol) in acetic acid(10 mL) potassium thiocyanate (0.37 g, 3.8 mmol) was added at ambienttemperature. After 30 min the hydrazine 4 (2.5 mmol) or hydrazinehydrochloride was added. Following stirring for 4 h at room temperaturethe reaction mixture was evaluated with TLC (CH₂Cl₂:MeOH=99:1). In caseno product formation could be observed, the mixture was warmed to 80° C.for 2 h. After adding 30 mL of water the precipitate was filtered offand washed with water. Mostly recrystallization from methanol affordedpure products, only in some cases further purification by columnchromatography (silica, CH₂Cl₂:MeOH=99:1) was necessary.

B.7. SYNTHESIS OF1-(3-CHLOROPHENYLAMINO)-2,3-DIHYDRO-4,5-DIPHENYL-1H-IMIDAZOLE-2-THIONE(9.26)

A mixture of benzoine (1.0 g, 0.0071 mol), KSCN (0.68 g, 0.0071 mol) and3-chlorophenylhydrazine×HCl (1.26 g, 0.0071 mol) was stirred in aceticacid (10 mL) for two days. The white precipitate formed was filtered off(0.4 g). Water (50 mL) was added and the precipitate formed was filteredoff. Recrystallization from MeOH/water (1:1) yielded 1.5 g (56%) of9.26.

B.8. CONVERSION OF METHOXYCARBONYL GROUPS INTO THE FREE ACIDS

The corresponding methoxycarbonyl substituted imidadazoline-2-thionederivative (1.33 mmol) (9.27, 9.34, 9.35, respectively) was stirred in a10% solution of NaOH (25 mL) for 6 h. After washing with CH₂Cl₂ removingimpurities, the aqueous layer was acidified. The precipitate formed wasfiltered off and dried.

B.9. SYNTHESIS OF5-(3-CARBOXAMIDOPHENYL)-1-(3-CHLOROPHENYLAMINO)-2,3-DIHYDRO-4-METHYL-1H-IMIDAZOLE-2-THIONE(9.38)

A mixture of the corresponding methoxycarbonyl substitutedimidazoline-2-thione (9.34) (1.33 mmol) was stirred in NH₃/MeOH for 2days. After removing the solvent the precipitate formed wasrecrystallized from MeOH/water (1:3) to yield 9.38 in 73% yield. ¹H- and¹³C-data of 1-amino-2,3-dihydro-1H-imidazoline-2-thiones 9 are collectedin Tables 3 and 4 from which the 2-thione structure was deduced.

1-(3-Chlorophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione(9.01)

[I. M. Lagoja, A. Van Aerschot, C. Hendrix, P. Herdewijn, Collect.Czech. Chem. Commun. 2000, 65, 1145–1155. ] Yield: 82 (%); mp: 215–217°C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.55; Exact Mass (C₁₆H₁₅ClN₃S):Calcd.: 316.0675 [M+H]⁺, Found: 316.0660.

1-(2-Chlorophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione(9.02)

[I. M. Lagoja, A. Van Aerschot, C. Hendrix, P. Herdewijn, Collect.Czech. Chem. Commun. 2000, 65, 1145–1155. ] Yield: 86 (%); mp: 220–221°C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.54; Exact Mass (C₁₆H₁₅ClN₃S):Calcd.: 316.0675 [M+H]⁺, Found: 316.0703.

2,3-Dihydro-1-(4-fluorophenylamino)-4-methyl-5-phenyl-1H-imidazole-2-thione(9.03)

Yield: 68 (%); mp: 228° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.53; ExactMass (C₁₆H₁₅FN₃S): Calcd.: 300.0971 [M+H]⁺, Found: 300.0996.

1-(4-Chlorophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione(9.04)

[J. G. Schantl, I. M. Lagoja, Heterocycles, 1997, 45, 691. ] Yield: 85(%); mp: 212–214° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.54; Exact Mass(C₁₆H₁₅ClN₃S): Calcd.: 316.0675 [M+H]⁺, Found: 316.0662.

5-(3-Bromophenyl)-1-(3-chlorophenylamino)-2,3-dihydro-4-methyl-1H-imidazole-2-thione(9.05)

Yield: 86 (%); mp: 196° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.52; ExactMass (C₁₆H₁₄BrClN₃S): Calcd.: 393.9790 [M+H]⁺, Found: 393.9839.

5-(4-Bromophenyl-1-(3-chlorophenylamino)-2,3-dihydro-4-methyl-1H-imidazole-2-thione(9.06)

Yield: 84 (%); mp: 220° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.52; ExactMass (C₁₆H₁₄BrCN₃S): Calcd.: 393.9790 [M+H]⁺, Found: 393.97788.

5-(3-Chlorophenyl)-1-(3-chlorophenylamino)-2,3-dihydro-4-methyl-1H-imidazole-2-thione(9.07)

Yield: 85 (%); mp: 204° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.52; ExactMass (C₁₆H₁₄Cl₂N₃S): Calcd.: 350.0855 [M+H]⁺, Found: 350.0271.

5-(4-Chlorophenyl)-1-(3-chlorophenylamino)-2,3-dihydro-4-methyl-1H-imidazole-2-thione(9.08)

Yield: 82 (%); mp: 225° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.52; ExactMass (C₁₆H₁₄Cl₂N₃S): Calcd.: 350.0855 [M+H]⁺, Found: 350.0356.

2,3-Dihydro-1-(3-chlorophenylamino)-5-(4-methoxyphenyl)-4-methyl-1H-imidazole-2-thione(9.09)

Yield: 88 (%); mp: 226° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.53; ExactMass (C₁₇H₁₇ClN₃OS): Calcd.: 346.0781 [M+H]⁺, Found: 350.0831.

1-(3-Chlorophenylamino)-2,3-dihydro-5-methyl-4-phenyl-1H-imidazole-2-thione(9.10)

Yield: 83 (%); mp: 238° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.53; ExactMass (C₁₆H₁₅ClN₃S): Calcd.: 316.0675 [M+H]⁺, Found: 316.0684.

1-(3-Chlorophenylamino)-2,3,4,5,6,7-hexahydro-1H-benzimidazole-2-thione(9.11)

Yield: 79 (%); mp: 148° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.52; ExactMass (C₁₃H₁₅ClN₃S): Calcd.: 280.0675 [M+H]⁺, Found: 280.0733.

2,3-Dihydro-4-methyl-5-phenyl-1-(phenylamino)-1H-imidazole-2-thione(9.12)

[J. G. Schantl, I. M. Lagoja, Heterocycles, 1997, 45, 691. ] Yield: 92(%); mp: 224–226° C. (MeO); Rf (CH₂Cl₂:MeOH=99:1): 0.49; Exact Mass(C₁₆H₁₅N₃S): Calcd.:282.1065 [M+H]⁺, Found: 282.1037.

2,3-Dihydro-1-(3,4-dimethylphenylamino)-4-methyl-5-phenyl-1H-imidazole-2-thione(9.13)

Yield: 62(%); mp: 228° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.53; ExactMass (C₁₆H₂₀N₃S): 310.1378 [M+H]⁺, Found: 310.1373.

1-(3-Bromophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione(9.14)

Yield: 52 (%); mp: 190° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.52; ExactMass (C₁₆H₁₄BrN₃S): Calcd.: 360.0170 [M+H]⁺, Found: 360.0168.

1-(3-Chloro-4-methylphenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione(9.15)

Yield: 32 (%); mp: 190° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.52; ExactMass (C₁₇H₁₆ClN₃S): Calcd.: 330.0832 [M+H]⁺, Found: 330.0834.

1-(2,5)-Dichlorophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione(9.16)

Yield: 60 (%); mp: 266° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.54; ExactMass (C₁₆H₁₄Cl₂N₃S): Calcd.: 350.0285 [M+H]⁺, Found: 350.0248.

2,3-Dihydro-4-methyl-1-(3-nitrophenylamino)-5-phenyl-1H-imidazole-2-thione(9.17)

Yield: 48(%); mp: 214° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.49; ExactMass (C₁₆H₁₄N₂O₂S): Calcd.: 327.0916 [M+H]⁺, Found: 327.0928.

2,3-Dihydro-1-(3-fluorophenylamino)-4-methyl-5-phenyl-1H-imidazole-2-thione(9.18)

Yield: 36 (%); mp: 226° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.53; ExactMass (C₁₆H₁₄FN₃S): Calcd.: 300.0971 [M+H]⁺, Found: 300.0933.

2,3-Dihydro-4-methyl-1-(3-methylphenylamino)-5-phenyl-1H-imidazole-2-thione(9.19)

Yield: 58 (%); mp: 206° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.53; ExactMass (C₁₇H₁₇N₃S): Calcd.: 296.1221 [M+H]⁺, Found: 296.1208.

2,3-Dihydro-4,5-dimethyl-1-(3-chlorophenylamino)-1H-imidazole-2-thione(9.20)

Yield: 87 (%); mp: 234° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.54; ExactMass (C₁₁H₁₃ClN₃S): Calcd.: 254.05187 [M+H]⁺, Found:. 254.0521.

2,3-Dihydro-4,5-dimethyl-1-(phenylamino)-1H-imidazole-2-thione (9.21)

Yield: 78 (%); mp: 217–219° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.53;Exact Mass (C₁₁H₁₄N₃S): Calcd.: 220.0908 [M+H]⁺, Found: 220.0844.

2,3-Dihydro-4,5-dimethyl-1-(3-methylphenylamino)-1H-imidazole-2-thione(9.22)

Yield: 85 (%); mp: 230° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.54; ExactMass (C₁₂H₁₆N₃S): Calcd.: 234.1065 [M+H]⁺, Found:. 234.1078.

2,3-Dihydro-4-isopropyl-1-(3-methylphenylamino)-5-phenyl-1H-imidazole-2-thione(9.23)

Yield: 46 (%); mp: 220–222° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.50;Exact Mass (C₁₉H₂₂N₃S): Calcd.: 324.1534 [M+H]⁺, Found:. 324.1524.

1-(3-Chlorophenylamino)-2,3-dihydro-4-ethyl-5-phenyl-1H-imidazole-2-thione(9.24)

Yield: 68 (%); mp: 116–118° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.52;Exact Mass (C₁₇H₁₇N₃ClS): Calcd.: 330.0831 [M+H]⁺, Found:. 330.0833.

2,3-Dihydro-4-ethyl-1-(3-methylphenylamino)-5-phenyl-1H-imidazole-2-thione(9.25)

Yield: 72 (%); mp: 202–204° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.53;Exact Mass (C₁₈H₂₀N₃S): Calcd.: 310.1377 [M+H]⁺, Found:. 310.1375.

1-(3-Chlorophenylamino)-2,3-dihydro-4,5-diphenyl-1H-imidazole-2-thione(9.26)

Yield: 56 (%); mp: 178–180° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.57;Exact Mass (C₂₁H₁₇N₃ClS): Calcd.: 378.0832 [M+H]⁺, Found: 378.0863.

1-(3-Chlorophenylamino)-2,3-dihydro-5-methoxycarbonyl-4-methyl-1H-imidazole-2-thione(9.27)

Yield: 68 (%); mp: 194–196° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.49;Exact Mass (C₁₂H₁₃N₃O₂ClS): Calcd.: 298.0417 [M+H]⁺, Found: 298.0421.

1-(3-Chlorophenylamino)-2,3-dihydro-5-hydroxycarbonyl-4-methyl-1H-imidazole-2-thione(9.28)

Yield: 52 (%); mp: 166–168° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.30;Exact Mass (C₁₁H₁₁N₃O₂ClS): Calcd.: 284.0261 [M+H]⁺, Found: 284.0261.

1-(3-Chlorophenylamino)-2,3-dihydro-4-methoxycarbonyl-5-methyl-1H-imidazole-2-thione(9.29)

Yield 75 (%); mp: 160–162° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.45; ExactMass (C₁₂H₁₃N₃O₂CIS): Calcd.: 298.0417 [M+H]⁺, Found: 298.0410.

2,3-Dihydro-1-(3,5-dimethylphenylamino)-4-methyl-5-phenyl-1H-imidazole-2-thione(9.30)

Yield: 82 (%); mp: 240–242° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.53;Exact Mass (C₁₈H₂₀N₃S): Calcd.: 310.1378 [M+H]⁺, Found: 310.1394.

1-(3-Methoxyphenylamino-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione(9.31)

Yield: 80 (%); mp: 184–186° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.53;Exact Mass (C₁₇H₁₈N₃OS): Calcd.: 312.1171 [M+H]⁺, Found: 312.1188.

1-(3-Chlorphenylamino)-5-(3-cyanophenyl)-2,3-dihydro-4-methyl-1H-imidazole-2-thione(9.32)

Yield: 84 (%); mp: 168–170° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1) 0.53; ExactMass (C₁₇H₁₄N₄ClS): Calcd.: 341.0628 [M+H]⁺, Found: 341.0675.

5-(3-Cyanophenyl)-2,3-dihydro-4-methyl-1-(3-methylphenylamino-1H-imidazole-2-thione(9.33)

Yield: 88 (%); mp: 160–162° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.53;Exact Mass (C₁₉H₁₇N₄S): Calcd.: 321.1174 [M+H]⁺, Found: 321.1152.

1-(3-Chlorphenylamino-2,3-dihydro-4-methyl-5-(3-methoxycarbonylphenyl-1H-imidazole-2-thione(9.34)

Yield: 90 (%); mp: 170–172° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.54;Exact Mass (C¹⁸H₁₇N₃ClO₂S): Calcd.: 374.0730 [M+H]⁺, Found: 374.0757.

2,3-Dihydro-4-methyl-1-(3-methylphenylamino)-5-(3-methoxycarbonylphenyl)-1H-imidazole-2-thione(9.35)

Yield: 80 (%); mp: 164–166° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.52;Exact Mass (C₁₉H₂₀N₃O₂S): Calcd.: 354.1276 [M+H]⁺, Found: 354.1305.

1-(3-Chlorphenylamino)-2,3-dihydro-5-(3-hydroxycarbonylphenyl)-4-methyl-1H-imidazole-2-thione(9.36)

Yield: 70 (%); mp: 170–172° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.34;Exact Mass (C₁₇H₁₅N₃ClO₂S): Calcd.: 360.0573 [M+H]⁺, Found: 360.0608.

2,3-Dihydro-5-(3-hydoxycarbonylphenyl)-4-methyl-1-(3-methylphenylamino)-1H-imidazole-2-thione(9.37)

Yield: 61 (%); mp: 166–168° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.33;Exact Mass (C₁₈H₁₈N₃O₂S): Calcd.: 340.1119 [M+H]⁺, Found: 340.1147.

5-(3-Carboxylamidophenyl)-1-(3-chlorphenylamino)-2,3-dihydro-4-methyl-1H-imidazole-2-thione(9.38)

Yield: 73 (%); mp: 164–166° C. (MeOH); Rf (CH₂Cl₂:MeOH=99:1): 0.35;Exact Mass (C₁₇H₁₆N₄OS): Calcd.: 359.0733 [M+H]⁺, Found: 359.0702.

B.10. SYNTHESIS OF 1-ARYLAMINO-2,3-DIHYDRO-1H-IMIDAZOLES: GENERALPROCEDURE

[J. G. Schantl, I. M. Lagoja, Heterocycles, 1998, 48, 929.]

A suspension of the respective 1-amino-2,3-dihydro-1H-imidazole-2-thione9 (2 mmol) in glacial acetic acid (10 mL) was stirred in an ice-bad.Upon dropwise addition of 30% hydrogen peroxide (1 mL, 9.76 mmol) thereaction mixture cleared up resulting in a clear brown solution. Afterstirring for another 15 min the reaction mixture was made alkaline (pH8–9) with 10% NaOH. The resulting precipitate was filtered off, washedwith cold water and recrystallized from water.

B.11. SYNTHESIS OF1-(ARYLAMINO)-5-(3-CARBOXAMIDOPHENYL)-4-METHYL-1H-IMIDAZOLINES FROM THECORRESPONDING1-(ARYLAMINO)-2,3-DIHYDRO-5-(3-METHOXYCARBONYLPHENYL)-4-METHYL-1H-IMIDAZOLE-2-THIONE

The corresponding methoxycarbonyl substituted imidadazoline-2-thionederivative (1.33 mmol) (9.34, 9.35, respectively) was treated with H₂O₂(30%) in a 10% solution of NaOH (25 ml) for 6 h. After washing withCH₂Cl₂ to remove impurities, the aqueous layer was acidified. Theprecipitate formed was filtered off and dried.

¹H- and ¹³C-data imidazoles 13 are collected in Tables 5 and 6.

1-(3-Chlorophenylamino)-4-methyl-5-phenyl-1H-imidazole: (13.01)

Yield: 88 (%); mp: 218° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.82; ExactMass (C₁₆H₁₅ClN₃): Calcd.: 284.0945 [M+H]⁺, Found: 284.0955.

5-(3-Bromophenyl)-1-(3-chlorophenylamino)-4-methyl-1H-imidazole: (13.02)

Yield: 52 (%); mp: 164° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.85; ExactMass (C₁₆H₁₃BrClN₃): Calcd.: 36.0059 [M+H]⁺, Found: 362.0062.

5-(3-Chlorophenyl)-1-(3-chlorophenylamino)-4-methyl-1H-imidazole:(13.03)

Yield: 66 (%); mp: 168° C. (MeOH); Rf (CH₂Cl₂: MeOH=9:1): 0.83; ExactMass (C₁₆H₁₃Cl₂N₃): Calcd.: 318.0565 [M+H]⁺, Found: 318.0616.

1-(3-Chlorophenylamino)-4,5,6,7-tetrahydro-1H-benzimidazole (13.04)

Yield: 76 (%); mp: 180° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.76; ExactMass (C₁₃H₁₄ClN₃): Calcd.: 248.0954 [M+H]⁺, Found: 248.0953.

4-Methyl-5-phenyl-1-phenylamino-1H-imidazole: (13.05)

[J. G. Schantl, I. M. Lagoja, Heterocycles, 1998, 48, 929. ] Yield: 86(%); mp: 165–167° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.84; Exact Mass(C₁₆H₁₆N₃): Calcd.: 250.1344 [M+H]⁺, Found: 250.1322.

4,5-Dimethyl-1-phenylamino-1H-imidazole: (13.06)

[J. G. Schantl, I. M. Lagoja, Heterocycles, 1998, 48, 929. ] Yield: 67(%); mp: 178° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): $$ 0.76; Exact Mass(C₁₁H₁₃N₃): Calcd.: 188.1188 [M+H]⁺, Found: 188.1153.

1-(3-Chlorophenylamino)-4,5-dimethyl-1H-imidazole: (13.07)

Yield: 82 (%); mp: 146° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.77; ExactMass (C₁₁H₁₃ClN₃): Calcd.: 222.0798 [M+H]⁺, Found: 222.0793.

4,5-Dimethyl-1-(3-methylphenylamino)-1H-imidazole: (13.08)

Yield: 86 (%); mp: 144° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.78; ExactMass (C₁₂H₁₆N₃): Calcd.: 202.1344 [M+H]⁺, Found: 202.1356.

4-Methyl-1-(3-methylphenylamino)-5-phenyl-1H-imidazole: (13.09)

Yield: 75 (%); mp: 159° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.84; ExactMass (C₁₇H₁₈N₃): Calcd.: 264.1500 [M+H]⁺, Found: 264.1536.

1-(4-Fluorophenylamino)-4-methyl-5-phenyl-1H-imidazole: (13.10)

Yield: 79 (%); mp: 155° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.76; ExactMass (C₁₆H₁₅FN₃): Calcd.: 268.1250 [M+H]⁺, Found: 268.1237.

4-Ethyl-1-(3-methylphenylamino)-5-phenyl-1H-imidazole: (13:11)

Yield: 81 (%); mp: 158–160° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.85; ExactMass (C₁₈H₂₀N₃): Calcd.: 278.1657 [M+H]⁺, Found: 278.1641.

1-(3-Chlorphenylamino)-5-methoxycarbonyl-4-methyl-1H-imidazole: (13.12)

Yield: 81 (%); mp: 138–140° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.85; ExactMass (C₁₈H₂₀N₃): Calcd.: 278.1657 [M+H]⁺, Found: 278.1641.

1-(3,5-Dimethylphenylamino)-4-methyl-5-phenyl-1H-imidazole (13.13)

Yield: 66 (%); mp: 154–156° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.86; ExactMass (C₁₈H₂₀N₃): Calcd.: 278.1657 [M+H]⁺, Found: 278.1636.

1-(3-Methoxyphenylamino)-4-methyl-5-phenyl-1H-imidazole (13.14)

Yield: 68 (%); mp: 156–158° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.84; ExactMass (C₁₇H₁₈N₃O): Calcd.: 280.1450 [M+H]⁺, Found: 280.1449.

1-(3-Chlorphenylamino)-5-(3-cyanophenyl)-4-methyl-1H-imidazole (13.15)

Yield: 75 (%); mp: 140–142° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.84; ExactMass (C₁₇H₁₄N₄Cl): Calcd.: 309.0907 [M+H]⁺, Found: 309.0911.

5-(3-Cyanophenyl)-4-methyl-1-(3-methylphenylamino)-1H-imidazole (13.16)

Yield: 70 (%); mp: 138–140° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.84; ExactMass (C₁₈H₁₇N₄): Calcd.: 289.1453 [M+H]⁺, Found: 289.1456.

5-(3-Carboxamidophenyl)-1-(3-chlorophenylamino)-4-methyl-1H-imidazole(13.17)

Yield: 84 (%); mp: 228–230° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.67; ExactMass (C₁₇H₁₆N₄): Calcd.: 327.1013 [M+H]⁺, Found: 327.1017.

5-(3-Carboxamidophenyl)-4-methyl-1-(3-methylphenylamino)-1H-imidazole(13.18)

Yield: 70 (%); mp: 220–222° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.66; ExactMass (C₁₈H₁₉N₄O): Calcd.: 307.1556 [M+H]⁺, Found: 307.1544.

1-(3-Chlorphenylamino)-5-(3-methoxycarbonylphenyl)-4-methyl-1H-imidazole(13.19)

Yield: 65 (%); mp: 172–174° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.80; ExactMass (C₁₈H₁₇N₃ClO₂): Calcd.: 342.1009 [M+H]+, Found: 342.1015.

1-(3-Chlorphenylamino)-5-(3-hydroxycarbonylphenyl)-4-methyl-1H-imidazole(13.20)

Yield: 77 (%); mp: 176–178° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.63; ExactMass (C₁₇H₁₅N₃ClO₂): 328.0853 [M+H]⁺, Found: 328.0854.

B.12. PREPARATION OF1-(3-CHLOROPHENYLAMINO)-4-METHYL-2-METHYLSULFANYL-5-PHENYL-1H-IMIDAZOLE(14.01)

A mixture of1-(3-chlorophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazoline-2-thione(9.01) (0.1 g, 0.37 mmol) and methyl iodide (1.19 g, 8.40 mmol) indichloromethane (5 mL) was heated under reflux for 1 h. Excess of methyliodide and solvent were removed in vacuo. Further purification wasachieved by recrystallisation from CH₂Cl₂/n-Hexane 1:1.

Yield: 98 (%); mp: 215° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.48; ¹H-NMR(DMSO-d6, 200 MHz): δ=2.33 (3H, s, 4-Me), 2.73 (3H, s, S-Me), 6.37 (1H,d, J=8.0 Hz, 6-H, N—Ar), 6.49 (1H, s, 2-H, N—Ar), 6.75 (1H, d, J=7.6 Hz,4-H, N—Ar), 7.67 (1H, dd, J¹=7.6 Hz, J²=8.0 Hz, 5-H, N—Ar), 7.31–7.34(5H, m, 5-Ph), 9.97 (NNH); ¹³C-NMR (DMSO-d6, 50 MHz): δ=9.1 (S-Me), 13.2(4-Me), 126.2, 127.2, 127.9, 128.1 (1-C, 2,6-CH, 3,5-CH, 4-CH 5-Ph),109.3, 110.8, 119.7, 129.1, 133.0, 144.5 (6-CH, 2-CH, 4-CH, 5-CH, 3-C,1-C N—Ar), 123.1, 129.8, 144.8 (5-C, 4-C, 2-C imidazole); Exact Mass(C₁₇H₁₇ClN₃S): Calcd.: 330.0832 [M+H]⁺, Found: 330.0837.

B.13. PREPARATION OF2-BENZYLSULFANYL-1-(3-CHLOROPHENYLAMINO)-4-METHYL-5-PHENYL-1H-IMIDAZOLE(14.02)

A mixture of1-(3-chlorophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazoline-2-thione(9.01) (0.2 g, 0.62 mmol) and benzylchloride (0.08 g, 0.62 mmol) inpyridine (5 mL) was heated under reflux for 3 h. After removing thesolvent the crude product was purified by column chromatography (silicagel, ethyl acetate/hexane=2:1.

Yield: 97 (%); mp: 130° C. (MeOH); Rf (CH₂Cl₂:MeOH=9:1): 0.21; ¹H-NMR(DMSO-d6, 200 MHz): δ=2.35 (3H, s, 4-Me), 4.12 (2H, s, CH₂S), 6.24 (1H,d, J=8.0 Hz, 6-H, N—Ar), 6.44 (1H, dd, J¹=7.6 Hz, J²=8.0 Hz, 5-H, N—Ar),6.55 (1H, s, 2-H, N—Ar), 6.83 (1H, d, J=7.6 Hz, 4-H, N—Ar), 7.02–7.33(10H, m, 5H 5-Ph+5H S-Bn), 10.0 (1H, s, NNH); ¹³C-NMR (DMSO-d6, 50 MHz):δ=13.9 (4-Me), 39.0 (CH₂S), 127.6, 128.3, 129.1, 137.6 (4-CH, 2,6-CH,3,5-CH, 1-C Bn), 127.7, 128.6, 128.8, 128.9, (4-CH, 2,6-CH, 3,5-CH, 1-C5-Ph), 110.7, 112.8, 121.1, 130.3, 134.9, 140.6 (6-CH, 2-CH, 4-CH, 5-CH,3-C, 1-C N—Ar), 130.2, 135.0, 147.9 (5-C, 4-C, 2-C imidazole); ExactMass (C₂₃H₂₁ClN₃S): Calcd.: 406.1145 [M+H]⁺, Found: 406.1165.

C. PHARMACOLOGICAL EXAMPLES

A rapid and automated assay procedure was used for the in vitroevaluation of anti-HIV agents. An HTLV-1 transformed T4-cell line MT-4,which was previously shown to be highly susceptible to and permissivefor HIV infection, served as the target cell line. Inhibition of theHIV-induced cytopathogenic effect was used as the end point. Theviabitlity of both HIV-and mock-infected cells was assessedspectrophotometrically via in situ reduction of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The50% cytotoxic concentration (CC₅₀ in μg/ml) was defined as theconcentration of compound that reduced the absorbance of themock-infected control sample by 50%. The percent protection achieved bythe compound in HIV-infected cells was calculated by the followingformula:

$\frac{\left( {OD}_{T} \right)_{HIV} - \left( {OD}_{C} \right)_{HIV}}{\left( {OD}_{C} \right)_{MOCK} - \left( {OD}_{C} \right)_{HIV}}\mspace{14mu}{expressed}\mspace{14mu}{in}\mspace{14mu}\%$whereby (OD_(T))_(HIV) is the optical density measured with a givenconcentration of the test compound in HIV-infected cells; (OD_(C))_(HIV)is the optical density measured for the control untreated HIV-infectedcells; (OD_(C))_(MOCK) is the optical density measured for the controluntreated mock-infected cells; all optical density values weredetermined at 540 nm. The dose achieving 50% protection according to theabove formula was defmed as the 50% inhibitory concentration (IC₅₀ inμg/ml). The ratio of CC₅₀ to IC₅₀ was defined as the selectivity index(SI). The compounds of formula (9 and 13) were shown to inhibit HIVeffectively. Examples of IC₅₀, CC₅₀ and SI values for inhibition ofproliferation of HIV by particular compounds of formula (I) are listedin table 7 herein below.

Examples of inhibition of cell proliferation by particular compounds offormula (I) can be found by looking at the respective CC₅₀ values in theMT-4 cell line.

Cells: MT-4 cells (Miyoshi et al., 1982) were grown and maintained inRPMI 1640 medium supplemented with 10% heat-inactivated fetal calfserum, 2 mM 1-glutamine, 0.1% sodium bicarbonate, and 20 œg ofgentamicin per ml.

Viruses: The HIV-1(NL4.3) strain (Adachi et al., 1986) is a molecularclone obtained from the National Institutes of Health (Bethesda, Md.).The HIV-2(ROD) (Barr,-Sinoussi et al., 1983) stock was obtained fromculture supernatant of HIV-2 infected cell lines.

References:

-   Adachi, A., Gendelman, H., Koenig, S., Folks, T., Willey, R.,    Rabson, A. and Martin, M (1986) Production of acquired    immunodeficiency syndrome-associated retrovirus in human and    nonhuman cells transfected with an infectious molecular clone, J.    Virol., 59, 284–291.-   Barr-Sinoussi, F., Chermann, J. C., Rey, F., Nugeyre, M. T.,    Chamaret, S., Gruest, J., Dauguet, C., Axler-Blin, C., V,zinet-Brun,    F., Rouzioux, C., Rozenbaum, W., Montagnier, L. (1983) Isolation of    a T-lymphotropic retrovirus from patient at risk for AIDS, Science    (Wash D.C.) 220, 868–871. Miyoshi, I., Taguchi, H., Kobonishi, I.,    Yoshimoto, S., Ohtsukj, Y., Shiraishi, Y. andAkagi,T. (1982) Type C    virus-producing cell lines derived from adult T cell leukemia, Gann    mongr, 28,219–228.

TABLE 7 Examples of IC₅₀, CC₅₀ and SI values for particular compounds 9and 13 HIV-1 (NL4.3 WT) HIV-2 IC₅₀ (ROD) cytotoxicity Compound No(μg/ml) SI IC₅₀ (μg/ml) SI CC₅₀ (μg/ml) 9.01 2.8 7.6 2.6 8.4 21.5 9.027.4 9.0 >65 <1 65 9.05 2.2 10.4 4.1 5.5 22.9 9.07 0.9 18.3 1.4 11.6 15.99.11 13.1 2.6 >34.0 <1 34.0 9.12 5.2 2.8 >14.7 <1 14.7 9.13 1.116.3 >17.9 <1 17.9 9.14 1.6 10.5 >17.1 <1 17.1 9.15 3.6 4.7 >16.9 <116.9 9.17 3.7 4.2 >15.4 <1 15.4 9.18 5.5 8.6 >47.3 <1 47.3 9.19 0.632.3 >20.7 <1 20.7 9.25 3.9 5.0 >19.8 <1 19.8 9.30 0.3 241.9 >65.3 <165.3 (Cryst)* 9.31 3.1 4.0 >12.3 <1 12.3 9.32 13.8 2.3 >32.1 <1 32.113.01 0.5 6.0 0.5 6.9 3.25 13.02 0.5 6.7 0.3 9.5 3.13 13.03 0.2 73.50.23 63.8 14.7 13.09 1.4 5.6 >7.6 <1 7.6 13.15 3.4 3.2 >10.9 <1 10.9*the compound crystallizes out during treatment at elevatedconcentrations, overestimating the toxic concentration.

TABLE 1 N-Aminoimidazole-2-thiones prepared according to the generalprocedure described in scheme 2.

R⁶ R¹ R⁵ 9.01 C₆H₅ CH₃ 3-ClC₆H₄ 9.02 C₆H₅ CH₃ 2-ClC₆H₄ 9.03 C₆H₅ CH₃4-FC₆H₄ 9.04 C₆H₅ CH₃ 4-ClC₆H₄ 9.05 3-BrC₆H₄ CH₃ 3-ClC₆H₄ 9.06 4-BrC₆H₄CH₃ 3-ClC₆H₄ 9.07 3-ClC₆H₄ CH₃ 3-ClC₆H₄ 9.08 4-ClC₆H₄ CH₃ 3-ClC₆H₄ 9.094-CH₃OC₆H₄ CH₃ 3-ClC₆H₄ 9.10 CH₃ C₆H₅ 3-ClC₆H₄ 9.11 —(CH₂)₄— 3-ClC₆H₄9.12 C₆H₅ CH₃ C₆H₅ 9.13 C₆H₅ CH₃ 3-CH₃-4-CH₃—C₆H₃ 9.14 C₆H₅ CH₃ 3-BrC₆H₄9.15 C₆H₅ CH₃ 3-Cl-4-CH₃C₆H₃ 9.16 C₆H₅ CH₃ 2-Cl-5-ClC₆H₃ 9.17 C₆H₅ CH₃3-NO₂C₆H₄ 9.18 C₆H₅ CH₃ 3-FC₆H₄ 9.19 C₆H₅ CH₃ 3-CH₃C₆H₄ 9.20 CH₃ CH₃3-ClC₆H₄ 9.21 CH₃ CH₃ C₆H₅ 9.22 CH₃ CH₃ 3-CH₃C₆H₄ 9.23 C₆H₅ (CH₃)₂CH3-CH₃C₆H₄ 9.24 C₆H₅ CH₃CH₂ 3-ClC₆H₄ 9.25 C₆H₅ CH₃CH₂ 3-CH₃C₆H₄ 9.26 C₆H₅C₆H₅ 3-ClC₆H₄ 9.27 CH₃OCO CH₃ 3-ClC₆H₄ 9.28 COOH CH₃ 3-ClC₆H₄ 9.29 CH₃CH₃OCO 3-ClC₆H₄ 9.30 C₆H₅ CH₃ 3-CH₃-5-CH₃C₆H₃ 9.31 C₆H₅ CH₃ 3-CH₃OC₆H₄9.32 3-CNC₆H₄ CH₃ 3-ClC₆H₄ 9.33 3-CNC₆H₄ CH₃ 3-MeC₆H₄ 9.34 3-MeOCOC₆H₄CH₃ 3-ClC₆H₄ 9.35 3-MeOCOC₆H₄ CH₃ 3-CH₃C₆H₄ 9.36 3-HOCOC₆H₄ CH₃ 3-ClC₆H₄9.37 3-HOCOC₆H₄ CH₃ 3-CH₃C₆H₄ 9.38 3-NH₂COC₆H₄ CH₃ 3-ClC₆H₄

TABLE 3 ¹H NMR N-Aminoimidazol-2-thiones 9 (DMSO-d6): 4 Subst 5 SubstN-Ar 1-NNH 3-NH 9.01 2.15(3H, s) 7.34–7.38(5H, m) 6.39(1H, d, J=8.4Hz,6-H), 6.42(1H, s, 9.30 12.55 2-H), 6.74(1H, d, J=8Hz, 4-H), 7.12(1H, dd,J¹=8Hz, J²=8.4Hz, 5-H) 9.02 2.15(3H, s) 7.23–7.48(5H, m) 6.08(1H, d,J=8Hz, 6-H), 6.72(1H, dd, 8.75 12.55 J¹=8Hz, J²=8.8Hz, 4-H), 7.04(1H,dd, J¹=8Hz, J²=8.8Hz, 5-H), 7.23(1H, d, J=8Hz, 3-H) 9.03* 2.14(3H, s)7.32–7.38(5H, m) 6.40, 6.44–6.91, 6.99(4H, AA′BB′ A=3,5 H, 8.94 12.49B=2, 6 H, J=8.2Hz) 9.04 2.14(3H, s) 7.30–7.35(m, 5H) 6.43, 6.47–7.12,7.35(4H, AA′BB′ A=3,5 H, 9.18 12.54 B=2, 6 H; J=8.4Hz) 9.05 2.16(3H, s)7.33–7.57(4H, m) 6.39(2H, m, 6-H, 2-H), 6.76(1H, d, J=7.8Hz, 9.31 12.614-H, 7.14(1H, dd, J¹=7.8Hz, J²=8.2Hz, 5-H) 9.06* 2.14(3H, s) 7.30,7.34–7.57, 7.60 6.38(2H, m, 6-H, 2-H), 6.75(1H, d, J=7.8Hz, 9.31 12.60(4H, AA′BB′ A=3, 5 H, B=2, 6 4-H, 7.12(1H, dd, J¹=7.8Hz, J²=8.2Hz, H;5-H) J=8.2Hz) 9.07 2.16(3H, s) 7.30–7.44(4H, m) 6.40(2H, m, 6-H, 2-H),6.75(1H, d, J=7.8Hz, 9.31 12.61 4-H, 7.13(1H, dd, J¹=7.8Hz, J²=8.2Hz,5-H) 9.08* 2.14(3H, s) 7.36, 7.40–7.43, 7.48 6.41(2H, m, 6-H, 2-H),6.75(1H, d, J=7.8Hz, 9.31 12.58 (4H, AA′BB′ A=3, 5 H, B=2, 6 4-H,7.08(1H, dd, J¹=7.8Hz, J²=8.2Hz, H; 5-H) J=8.8Hz) 9.09* 2.11(3H, s)3.72(s, MeO) 6.38(2H, m, 6-H, 2-H), 6.73(1H, d, J=8Hz, 9.25 12.45 6.90,6.95–7.26, 7.30(4H, 4-H, 7.12(1H, dd, J¹=8.3Hz, J²=8.2Hz, AA′BB′ A=3,5H, 5-H) B=2,6 H; J=8.6Hz) 9.10 7.34(1H, t, J=7.8Hz), 2.19(3H, s)6.52(1H, d, J=8.4Hz, 6-H), 6.56(1H, s, 9.31 12.72 7.46(2H, dd, J¹=7.2Hz,2-H), 6.85(1H, d, J=8Hz, 4-H, 7.22(1H, J²=7.8Hz), 7.55, 7.60 dd, J¹=8Hz,J²=8.4Hz, 5-H) (2H, d, J=7.2Hz) 9.11 1.70(4H, m, 5,6CH₂CH₂), 6.44(2H, m,6-H, 2-H), 6.81,(1H, d, J=8Hz, 9.11 12.14 2.23(2H, m, 4-CH₂), 2.37(2H,4-H), 7.15(1H, dd, J¹=8.2Hz, J²=8Hz, m, 5-CH₂) 5-H) 9.12 2.14(3H, s)7.30–7.37(5H, m) 6.42(2H, d, J=8.4Hz, 2,6-H), 6.70(1H, t, 8.95 12.47J=7.6Hz, 4-H), 7.09(2H,(t), J=7.6Hz, 3, 5-H) 9.13 2.15(3H, s)7.31–7.40(5H, m) 2.05(3H, s, 4-Me), 2.07(3H, s, 3-Me), 8.67 12.436.12(1H, d, J=8Hz, 6-H), 6.31(1H, s, 2- H), 6.84(1H, d, J=8.2Hz, 5-H)9.14 2.15(3H, s) 7.30–7.36(5H, m) 6.41(1H, d, J=8.4Hz, 6-H), 6.57(1H, s,9.28 12.54 2-H), 6.87(1H, d, J=8Hz, 4-H), 7.06(1H, dd, J¹=8.4Hz J²=8Hz,5-H) 9.15 2.15(3H, s) 7.32–7.38(5H, m) 2.15(3H, s, 4-Me) 9.09 12.456.33(1H, d, J=8.4Hz, 6-H), 6.45(1H, s, 2-H), 7.06(1H, d, J=8.4Hz, 5-H)9.16 2.15(3H, s) 7.30–7.46(5H, m) 6.03(1H, d, J=2.4Hz, 6-H), 6.75(1H,d×d, 9.12 12.62 J=2.4Hz, J=8.6Hz, 4-H), 7.26–7.30 (1H, m, 3-H) 9.172.16(3H, s) 7.36–7.44(5H, m) 6.85(1H, d, J=7.8Hz, 6-H), 7.22(1H, s, 9.7112.45 2-H), 7.36–7.44(1H, m, 5-H), 7.56(1H, d, J=7.8Hz, 4-H) 9.182.19(3H, s) 7.31–7.39(5H, m) 6.12(1H,(d), 2-H), 6.27(1H,(d), 6-H), 9.4312.59 6.52(1H,(t), 4-H), 7.07–7.19(1H, m, 5- H) 9.19 2.15(3H, s)7.35–7.40(5H, m) 2.48(3H, s, Me), 8.85 12.45 6.18(1H, d, J=8.2Hz, 6-H),6.29(1H, s, 2-H), 6.52(1H, d, J=8.2Hz, 4-H), 6.97 (1H,(t), J=8.2Hz, 5-H)9.20 1.90(3H, s) 2.01(3H, s) 6.44(2H, m, 6-H, 2-H), 6.80,(1H, d, J=8Hz,9.13 12.80 4-H), 7.18(1H, dd, J¹=8Hz, J²=8.4Hz, 5-H) 9.21 1.89(3H, s)2.01(3H, s) 6.47,(2H, d, J=8.2Hz, 2,6-H), 6.76(1H, 8.97 12.02 t,J=7.4Hz, 4-H), 7.15(2H, dd, J¹=7.4Hz, J²=8.2Hz, 3,5-H) 9.22 1.89(3H, s)2.02(3H, s) 2.19(3H, s, Me) 8.70 12.00 6.24(1H, d, J=8.2Hz, 6-H),6.32(1H, s, 2-H), 6.60(1H, d, J=8.2Hz, 4-H), 7.04 (1H,(t), J=8.2Hz, 5-H)9.23 1.21(6H,d, J=7Hz, 2×CH₃), 7.32–7.36(5H, m) 2.16(3H, s, Me) 8.7612.50 2.87(1H, q×q, J=7Hz, 6.14(1H, d, J=8.0Hz, 6-H), 6.29(1H, s, CH)2-H), 6.50(1H, d, J=8.0Hz, 4-H), 6.96 (1H,(t), J=8.0Hz, 5-H) 9.241.17(3H, t, J=7.6Hz), 7.30–7.35(5H, m) 6.40(2H, m, 6-H, 2-H), 6.73,(1H,d, J=8Hz, 9.24 12.57 2.49(2H, q, J=7.6Hz) 4-H), 7.16(1H, dd, J¹=8.5Hz,J²=8Hz, 5-H) 9.25 1.17(3H, t, J=7.6Hz), 7.28–7.34(5H, m) 2.15(3H, s, Me)8.81 12.48 2.49(2H, q, J=7.6Hz) 6.13(1H, d, J=8.0Hz, 6-H), 6.28(1H, s,2-H), 6.49(1H, d, J=8.0Hz, 4-H), 6.92 (1H,(t), J=8.0Hz, 5-H) 9.267.11–7.58(11H, m, 6.43(1H, d, J=8.0Hz, 6-H), 6.52(1H, s, 9.29 13.03 Ph4-C+Ph 5-C+5-H N-Ar) 2-H), 6.78,(1H, d, J=8Hz, 4-H) 9.27 3.64(3H, s,CH₃CO₂) 2.35(3H, s) 6.47(2H, m, 6-H, 2-H), 6.77,(1H, d, J=8Hz, 9.1213.02 4-H), 7.23(1H, dd, J¹=8.5Hz, J²=8Hz, 5-H) 9.28 10.7(1H, s, br, OH)2.15(3H, s) 6.44(2H, m, 6-H, 2-H), 6.75,(1H, d, J=8Hz, 9.06 12.90 4-H),7.15(1H, dd, J¹=8.5Hz, J²=8Hz, 5-H) 9.29 2.08(3H, s) 3.67(3H, s, CH₃CO₂)6.74(2H, m, 6-H, 2-H), 6.85,(1H, d, J=8Hz, 8.74 10.28 4-H), 7.22(1H, dd,J¹=8.5Hz, J²=8Hz, 5-H) 9.30 2.16(3H, s) 7.32–7.37(5H, m) 2.11(6H, s,2×CH₃), 6.06(2H, s, 2,6-H), 8.76 12.43 6.35(1H, s, 4-H) 9.31 2.15(3H, s)7.33–7.38(5H, m) 3.63(3H, s, CH₃), 5.96(1H, s, 2H), 6.02 8.95 12.47 (1H,d, J=8.2Hz, 6-H), 6.30(1H, d, J=8.2Hz, 4-H), 7.00(1H,(t), J=8.2Hz, 5-H)9.32 2.18(3H, s) 7.58–7.78(3H, m, 4,5,6-H), 7.84 6.42(2H, m, 6-H, 2-H),6.74,(1H, d, J=8Hz, 9.34 12.68 (1H, s, 2-H) 4-H), 7.10(1H, dd, J¹=8.5Hz,J²=8Hz, 5-H) 9.33 2.16(3H, s) 7.57(1H,(t), J=7.6Hz, 5-H), 2.18(3H, s,Me) 8.93 12.60 7.70–7.77(2H, m, 4,6-H), 7.86 6.18(1H, d, J=8.2Hz, 6-H),6.31(1H, s, (1H, s, 2-H) 2-H), 6.54(1H, d, J=8.2Hz, 4-H), 6.98 (1H,(t),J=8.2Hz, 5-H) 9.34 2.17(3H, s) 3.80(3H, s, MeCO₂) 6.42(2H, m, 6-H, 2-H),6.74,(1H, d, J=8Hz, 9.30 12.61 7.54(1H,(t), J=7.6Hz, 5-H), 4-H),7.13(1H, dd, J¹=8.5Hz, J²=8Hz, 7.66(1H, d, J=8Hz, 6-H), 7.90 5-H) (1H,d, J=7.6Hz, 4-H), 7.94 (1H, s, 2-H) 9.35 2.17(3H, s) 3.79(3H, s, MeCO₂)2.22(3H, s, Me) 9.30 12.54 7.54(1H,(t), J=7.6Hz, 5-H), 6.18(1H, d,J=8.1Hz, 6-H), 6.31(1H, s, 7.66(1H, d, J=8Hz, 6-H), 7.90 2-H), 6.54(1H,d, J=8.1Hz, 4-H), 6.98 (1H, d, J=7.6Hz, 4-H), 7.94 (1H,(t), J=8.1Hz,5-H) (1H, s, 2-H) 9.36 2.16(3H, s) 13.09(s, br COOH) 6.40(2H, m, 6-H,2-H), 6.74,(1H, d, J=8Hz, 9.33 12.60 7.51(1H,(t), J=7.8Hz, 5-H), 4-H),7.12(1H, dd, J¹=8.2Hz, J²=8Hz, 7.62(1H, d, J=8Hz, 6-H), 7.87 5-H) (1H,d, J=7.6Hz, 4-H), 7.94 (1H, s, 2-H) 9.37 2.15(3H, s) 13.00(s, br COOH)2.17(3H, s, Me) 8.90 12.51 7.49(1H,(t), J=7.8Hz, 5-H), 6.19(1H, d,J=8.1Hz, 6-H), 6.30(1H, s, 7.63(1H, d, J=8Hz, 6-H), 7.85 2-H), 6.52(1H,d, J=8.1Hz, 4-H), 6.95 (1H, d, J=7.6Hz, 4-H, 7.95 (1H,(t), J=8.1Hz, 5-H)(1H, s, 2-H) 9.38 2.16(3H, s) 10.20(s, br, CONH₂) 6.40(2H, m, 6-H, 2-H),6.78,(1H, d, J=8Hz, 9.33 12.62 7.54–63(2H, m, 5-H, 4-H), 7.10(1H, dd,J¹=8.2Hz, J²=8Hz, 5-H) 6-H), 7.87–7.93 (2H, m, 4-H, 2H) *determinationof J is based on the assumption of an AB quartett [E. D. Becker in:“High Resolution NMR, Theory and Chemical Application”, Academic Press,New York, 1969, 169.]

TABLE 4 ¹³C NMR N-Aminoimidazol-2-thiones 9(DMSO-d6): 4 Subst 5 SubstN-Ar Imidazole 9.01 10.1 127.6, 128.2, 128.6, 129.0 111.2, 111.9, 119.1,130.8, 133.6, 120.2, 126.6, 161.8 (1-C, 4-CH, 2,6-CH, 3,5-CH)148.9(6-CH, 2-CH, 4-CH, 5-CH, 3-C, (4-C, 5-C, 2-C) 1-C) 9.02 10.1 127.7,128.1, 128.5, 129.1 113.2, 117.3, 120.4, 127.8, 129.1, 120.0, 126.7,161.9 (1-C, 4-CH, 2,6-CH, 3,5-CH) 142.8(6-CH, 2-C, 4-CH, 5-CH, 3-CH,(4-C, 5-C, 2-C) 1-C) 9.03 10.1 127.8, 128.1, 128.5, 129.1 113.8(d,J^(F)=7.6Hz), 115.5(d, J^(F)=23Hz), 120.0, 126.7, 161.7 (1-C, 4-CH,2,6-CH, 3,5-CH) 143.8, 158.7(2,6-CH, 3,5-CH, (4-C, 5-C, 2-C) 1-C, 4-C)9.04 10.1 127.7, 128.1, 128.5, 129.1 114.1, 122.9, 128.8, 146.3 120.0,126.7, 161.8 (1-C, 4-CH, 2,6-CH, 3,5-CH) (2,6-CH, 4-C, 3,5-CH, 1-C)(4-C, 5-C, 2-C) 9.05 10.1 121.3, 128.0, 129.9, 130.7, 130.9, 111.2,111.9, 119.3, 130.8, 133.7, 121.7, 125.0, 162.1 131.3 148.7(6-CH, 2-CH,4-CH, 5-CH, 3-C, (4-C, 5-C, 2-C) (3-C, 1-C, 6-CH, 4-CH, 2-CH, 5-CH) 1-C)9.06 10.1 120.8, 126.8, 130.9, 131.6 111.2, 111.9, 119.3, 130.8, 133.7,121.6, 125.4, 162.0 (4-C, 1-C, 2,6-CH, 3,5-CH) 148.7(6-CH, 2-CH, 4-CH,5-CH, 3-C, (4-C, 5-C, 2-C) 1-C) 9.07 10.1 127.6, 128.0, 128.5, 129.6,130.5, 111.2, 111.9, 119.3, 130.8, 133.7, 121.3, 125.1, 162.1 133.2148.7 (4-C, 5-C, 2-C) (6-CH, 4-CH, 5-CH, 2-CH, 1-C, 3-C) (6-CH, 2-CH,4-CH, 5-CH, 3-C, 1-C) 9.08 10.1 126.5, 128.7, 130.7, 132.9 111.2, 111.9,119.3, 130.8, 133.7, 120.7, 125.4, 162.0 (4-C, 2,6-C, 3,5-C, 1-C) 148.7(4-C, 5-C, 2-C) (6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C) 9.09 10.0 55.2(CH₃O);114.1, 119.3, 130.5, 159.2 111.1, 111.9, 119.0, 130.7, 133.6, 119.8,126.5, 161.4 (2,6-CH, 1-C, 3,5-CH, 159.2(4-C) 148.9(6-CH, 2-CH, 4-CH,5-CH, 3-C, (4-C, 5-C, 2-C) 1-C) 9.10 126.7, 127.7, 9.2 111.3, 112.1,119.7, 130.0, 133.8, 122.0, 124.0, 162.2 128.9, 129.0 148.8(6-CH, 2-CH,4-CH, 5-CH, 3-C, (4-C, 5-C, 2-C) (2,6-CH, 4-CH, 1-C) 1-C, 3,5-CH) 9.1119.3, 20.2, 21.6, 21.8(7-CH₂, 4-CH₂, 5-CH₂, 6-CH₂) 111.2, 112.1, 119.5,130.9, 133.7, 120.9, 125.0, 161.1 149.2(6-CH, 2-CH, 4-CH, 5-CH, 3-C,(4-C, 5-C, 2-C) 1-C) 9.12 10.1 127.9, 128.0, 128.5, 128.6 112.5, 119.4,129.1, 147.3 119.9, 126.8, 161.8 (1-C, 4-CH, 2,6-CH, 3,5-CH) (2,6-CH,4-CH, 3,5-CH, 1-C) (4-C, 5-C, 2-C) 9.13 10.1 127.9, 128.0, 128.4, 129.118.5(4-Me), 19.8(3-Me), 119.7, 127.0, 161.8 (1-C, 4-CH, 2,6-CH, 3,5-CH)110.0, 114.1, 126.8, 129.9, 136.5, (4-C, 5-C, 2-C) 145.4(6-CH, 2-CH,4-C, 5-CH, 3-C, 1- C) 9.14 10.1 127.3, 128.2, 128.6, 129.0 111.5, 114.8,122.0, 122.1, 131.1, 120.2, 126.6, 161.8 (1-C, 4-CH, 2,6-CH, 3,5-CH)149.0 (4-C, 5-C, 2-C) (6-CH, 2-CH, 4-CH, 3-C, 5-CH, 1-C) 9.15 10.1127.7, 128.1, 128.6, 129.0 18.6(4-Me), 120.1, 125.7, 161.7 (1-C, 4-CH,2,6-CH, 3,5-CH) 111.6, 112.6, 126.6, 131.6, 133.5, (4-C, 5-C, 2-C)146.7(6-CH, 2-CH, 4-C, 5-CH, 3-C, 1- C) 9.16 10.1 127.4, 128.3, 128.7,129.1 106.3, 114.1, 118.7, 130.6, 148.5, 120.4, 126.5, 161.8 (1-C, 4-CH,2,6-CH, 3,5-CH) 148.7 (4-C, 5-C, 2-C) (2-CH, 4-CH, 6-CH, 5-CH, 3-C, 1-C)9.17 10.1 127.9, 128.0, 128.5, 129.1 112.5, 115.8, 119.8, 131.0, 132.3,120.3, 126.3, 161.8 (1-C, 4-CH, 2,6-CH, 3,5-CH) 143.9 (4-C, 5-C, 2-C)(6-CH, 2-CH, 4-C, 5-CH, 3-C, 1-C) 9.18 10.6 127.9, 128.0, 128.5, 129.199.2(d, J^(F)=20Hz, 2-CH), 105.9(d, 116.2, 127.6, 160.8 (1-C, 4-CH,2,6-CH, 3,5-CH) J^(F)=20Hz, 4-CH), 108.5(6-CH), 130.8 (4-C, 5-C, 2-C)(d, J^(F)=10Hz, 5-CH), 149.4(d, J^(F)=10Hz, 1-C), 165.6(3-C) 9.19 10.1128.2, 128.6, 128.7, 129.1 21.3(3-Me) 119.8, 126.9, 161.8 (1-C, 4-CH,2,6-CH, 3,5-CH) 109.6, 113.1, 120.3, 128.9, 138.1, (4-C, 5-C, 2-C) 147.4(6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C) 9.20 9.2 7.8 111.1, 111.9, 119.1,130.9, 133.8, 117.7, 122.2, 160.8 149.1(6-CH, 2-CH, 4-CH, 5-CH, 3-C,(4-C, 5-C, 2-C) 1-C) 9.21 9.1 7.9 112.5, 119.8, 129.1, 147.5 117.5,122.4, 160.7 (2,6-CH, 4-CH, 3,5-CH, 1-C) (4-C, 5-C, 2-C) 9.22 9.13 7.921.3(3-Me) 117.3, 122.4, 160.7 109.7, 113.0, 120.7, 129.0, 138.3, (4-C,5-C, 2-C) 147.5 (6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C) 9.23 21.8(2 × CH₃),128.3, 128.5, 129.5, 129.7 21.3(3-Me) 125.7, 127.9, 162.2 24.1(CH)(4-CH, 2,6-CH, 1-C, 3,5-CH) 109.5, 113.2, 120.3, 128.8, 138.0, (4-C,5-C, 2-C) 147.4 (6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C) 9.24 13.7(CH₃), 17.6127.6, 128.4, 128.6, 129.3 111.1, 111.9, 119.1, 130.8, 133.6, 125.8,126.3, 162.1 (CH₂) (1-C, 4-CH, 2,6-CH, 3,5-CH) 148.9 (4-C, 5-C, 2-C)(6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C) 9.25 13.8(CH₃), 17.6 127.9, 128.2,128.5, 129.3. 21.3(3-Me) 125.5, 126.5, 162.0 (CH₂) (1-C, 4-CH, 2,6-CH,3,5-CH) 109.6, 113.1, 120.3, 128.9, 138.1, (4-C, 5-C, 2-C) 147.4 (6-CH,2-CH, 4-CH, 5-CH, 3-C, 1-C) 9.26 126.5, 128.0, 127.8, 128.0, 128.5,128.8 111.2, 112.1, 119.3, 130.8, 133.6, 123.3, 126.3, 162.9 129.3,130.4 (1-C, 4-CH, 2,6-CH, 3,5-CH) 148.8 (4-C, 5-C, 2-C) (2,6-CH, 4-CH,1- (6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C) C, 3,5-CH) 9.27 51.2(CH₃), 164.611.3 111.0, 111.7, 118.8, 130.2, 134.0, 115.7, 133.0, 158.0 (C═O) 148.6(4-C, 5-C, 2-C) (6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C) 9.28 164.7(C═O) 11.4111.4, 112.2, 119.1, 130.6, 134.0, 116.8, 133.5, 159.2 149.2 (4-C, 5-C,2-C) (6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C) 9.29 17.5 51.5(CH₃), 170.6(C═O)111.3, 111.9, 119.5, 131.0, 133.9, 119.4, 125.1, 162.6 149.4 (4-C, 5-C,2-C) (6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C) 9.30 10.2 128.0, 128.4, 128.5,129.1 21.2(3,5 Me) 119.7, 126.9, 161.8 (4-CH, 1-C, 2,6-CH, 3,5-CH)110.3, 121.4, 137.9, 147.4 (4-C, 5-C, 2-C) (2,6-CH, 3,5-C, 4-CH, 1-C)9.31 10.1 127.8, 128.0, 128.5, 129.1 54.9(3MeO) 119.9, 126.8, 161.9(1-C, 4-CH, 2,6-CH, 3,5-CH) 98.8, 104.6, 105.3, 129.9, 148.8, (4-C, 5-C,2-C) 160.2 (2-CH, 6-CH, 4-CH, 5-CH, 1-C, 3-C) 9.32 10.1 111.8, 118.6,128.9, 129.9, 131.7, 111.2, 112.0, 119.4, 130.9, 133.7, 121.8, 124.6,162.3 132.2, 133.6 148.6 (4-C, 5-C, 2-C) (3-C, CN, 1-C, 5-CH, 4-CH,2-CH, 6- (6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C) CH) 9.33 10.1 111.7, 118.7,129.2, 129.9, 131.6, 21.3(3-Me) 121.5, 124.8, 162.4 132.3, 133.6 109.7,113.2, 120.6, 128.9, 138.3, (4-C, 5-C, 2-C) (3-C, CN, 1-C, 5-CH, 4-CH,2-CH, 6- 147.0 CH) (6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C) 9.34 10.052.3(MeO), 166.0(CO) 111.2, 112.0, 119.2, 130.8, 133.6, 121.0, 125.8,162.1 127.2, 128.7, 129.2, 129.6, 130.7, 148.8 (4-C, 5-C, 2-C) 133.6(6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C) (1-C, 4-CH, 5-CH, 2-CH, 6-CH, 3-C)9.35 10.0 52.3(MeO), 166.0(CO) 21.1(3-Me) 121.0, 127.8, 162.2 127.2,128.7, 129.1, 129.5, 131.3, 133.7 109.7, 113.2, 120.5, 128.9, 138.5,(4-C, 5-C, 2-C) (1-C, 4-CH, 5-CH, 2-CH, 6-CH, 3-C) 147.0 (6-CH, 2-CH,4-CH, 5-CH, 3-C, 1-C) 9.36 10.1 167.1(CO₂H) 111.2, 112.1, 119.3, 130.8,133.6, 120.9, 125.7, 162.0 128.0, 128.6, 128.9, 129.7, 131.3, 148.8(4-C, 5-C, 2-C) 133.3 (6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C) (4-CH, 1-C,5-CH, 2-CH, 3-C, 6-CH) 9.37 10.1 167.1(CO₂H) 21.1(3-Me) 121.0, 126.0,162.0 128.2, 128.9, 129.4, 129.7, 131.2, 109.7, 113.3, 120.5, 128.9,138.1, 147.3 (4-C, 5-C, 2-C) 133.3 (6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C)(4-CH, 1-C, 5-CH, 2-CH, 3-C, 6-CH) 9.38 10.1 165.9(CONH₂) 111.2, 112.0,119.2, 130.7, 133.6, 121.8, 126.3, 162.0 128.6, 129.2, 129.6, 130.8,131.4, 148.7 (4-C, 5-C, 2-C) 133.5 (6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C)(1-C, 4-CH, 2-CH, 5-CH, 3-C, 6-CH)

TABLE 5 ¹H NMR N-Aminoimidazoles 13 (DMSO-d6): 4 Subst 5 Subst N-Ar 2-H1-NNH 13.01 2.35(3H, s) 7.42–7.49(5H, m) 6.52(1H, d, J=8.2Hz, 6-H),6.62(1H, s, 2-H), 7.51 9.45 6.86(1H, d, J=8Hz, 4-H), 7.17(1H, dd,J¹=8Hz, J²=8.2Hz, 5-H) 13.02 2.21(3H, s) 7.31–7.55(4H, m) 6.30(2H, m,6-H, 2-H), 6.77(1H, d, J=8Hz, 7.81 9.65 4-H), 7.14(1H, dd, J¹=8.1Hz,J²=8.3Hz, 5-H) 13.03 2.23(3H, s) 7.31–7.43(4H, m) 6.30(2H, m, 6-H, 2-H),6.76(1H, d, J=8.1Hz, 7.82 9.66 4-H), 7.14(1H, dd, J¹=8Hz, J²=8.2Hz, 5-H)13.04 1.69(4H, m, 5,6-CH₂CH₂), 6.35(2H, m, 6-H, 2-H), 6.83(1H, d, J=8Hz,7.55 9.49 2.25(2H, m, 4-CH₂), 2.48(2H, m, 7-CH₂) 4-H), 7.22(1H, dd,J¹=8Hz, J²=8.4Hz, 5-H) 13.05 2.22(3H, s) 7.28–7.37(5H, m) 6.33(2H, d,J=8.2Hz, 2,6-H), 6.72(1H, t, J=7.3Hz, 7.72 9.36 4-H), 7.11(2H, dd,J¹=7.3, J²=8.2Hz, 3,5H) 13.06 1.89(3H, s) 2.06(3H, s) 6.36(1H, d,J=8.2Hz, 2,6-H), 6.81(t, J=7.3Hz, 7.52 9.14 4-H), 7.19(dd, J¹=7.3,J²=8.2Hz) 13.07 1.91(3H, s) 2.07(3H, s) 6.35(2H, m, 6-H, 2-H), 6.86(1H,d, J=8.1Hz, 7.56 9.43 4-H), 7.22(1H, dd, J¹=8Hz, J²=8.4Hz, 5-H) 13.081.89(3H, s) 2.06(3H, s) 2.48(3H, s, 3-Me) 7.50 9.06 6.15(1H, d, J=8.2Hz,6-H), 6.23(1H, s, 2-H), 6.62(1H, d, J=8.2Hz, 4-H), 7.06(1H,(t), J=8.2Hz,5-H) 13.09 2.13(3H, s) 7.30–7.33(5H, m) 2.22(3H, s, 3-Me) 7.71 9.276.17(2H, m, 2-H, 6-H), 6.57(1H, d, J=8.2Hz, 4-H), 6.99(1H,(t), J=8.2Hz,5-H) 13.10 2.21(3H, s) 7.28–7.37(5H, m) 6.32–6.36, 6.91–7.00(AA′ BB′)7.74 9.31 13.11 1.17(3H, t, J=7.6Hz), 2.49 7.25–7.34(5H, m) 2.13(3H, s,Me) 7.69 9.21 (2H, q, J=7.6Hz) 6.09(1H, d, J=8.0Hz, 6-H), 6.19(1H, s,2-H), 6.52(1H, d, J=8.0Hz, 4-H), 7.02(1H,(t), J=8.0Hz, 5-H) 13.122.39(3H, s) 3.78(3H, s) 6.35(2H, m, 6-H, 2-H), 6.86(1H, d, J=8.1Hz, 7.959.19 4-H), 7.22(1H, dd, J¹=8Hz, J²=8.4Hz, 5-H) 13.13 2.21(3H, s)7.32–7.36(5H, m) 2.09(6H, s, 2×CH₃), 5.98(2H, s, 2,6-H), 6.38 7.66 9.25(1H, s, 4-H) 13.14 2.22(3H, s) 7.28–7.38(5H, m) 3.62(3H, s, 3-MeO) 7.739.35 5.88(1H, s, 2-H), 5.95(1H, d, J=8.2Hz, 6-H), 6.34(1H, d, J=8.2Hz,4-H), 7.02(1H,(t), J=8.2Hz, 5-H) 13.15 2.24(3H, s) 7.57(1H,(t) J=7.6Hz,5-H), 7.72 6.32(2H, m, 6-H, 2-H), 6.78(1H, d, J=7.6Hz, 7.86 9.72 (3H, m,2,4,6-H) 4-H), 7.12(1H, dd, J¹=7.6Hz, J²=8.4Hz, 5-H) 13.16 2.18(3H, s)7.55(1H,(t) J=7.6Hz, 5-H), 7.71 2.13(3H, s, Me) 7.84 9.32 (2H, m,4,6-H), 7.79(1H, s, 2-H) 6.11(1H, d, J=8.0Hz, 6-H), 6.20(1H, s, 2-H),6.53(1H, d, J=8.0Hz, 4-H), 7.00(1H,(t), J=8.0Hz, 5-H) 13.17 2.29(3H, s)7.42(m, 4H), 7.90(2H, m) 6.36(2H, m, 6-H, 2-H), 6.72(1H, d, J=7.8Hz,7.88 10.11 4-H), 7.04(1H, dd, J¹=7.8Hz, J²=8.4Hz, 5-H) 13.18 2.29(3H, s)7.50(m, 4H), 7.84(2H, m) 2.12(3H, s, Me) 8.00 9.94 6.24(1H, d, J=8.0Hz,6-H), 6.27(1H, s, 2-H), 6.42(1H, d, J=8.0Hz, 4-H), 7.00(1H,(t), J=8.0Hz,5-H) 13.19 2.24 12.61(1H, s, br, COOH) 6.30(2H, m, 6-H, 2-H), 6.76(1H,d, J=8Hz, 7.92 9.69 7.51(1H,(t), J=7.8Hz, 5-H), 7.60 4-H), 7.12(1H, dd,J¹=8.2Hz, J²=8Hz, 5-H) (1H, d, J=8Hz, 6-H, 7.82(1H, d, J=7.6Hz, 4-H),7.86(1H, s, 2-H) 13.20 2.24(3H, s) 12.73(1H, s, br, COOH) 6.32(2H, m,6-H, 2-H), 6.75(1H, d, J=8Hz, 7.93 9.68 7.53(1H,(t), J=7.8Hz, 5-H), 7.644-H), 7.14(1H, dd, J¹=8.2Hz, J²=8Hz, 5-H) (1H, d, J=8Hz, 6-H, 7.83(1H,d, J=7.6Hz, 4-H), 7.87(1H, s, 2-H) *determination of J is based on theassumption of an AB quartett [E. D. Becker in: “High Resolution NMR,Theory and Chemical Application”, Academic Press, New York, 1969, 169.]

TABLE 6 ¹³C NMR N-Aminoimidazoles 13(DMSO-d6): 4 Subst 5 Subst N-ArImidazole 13.01 10.5 127.3, 128.9, 129.8, 129.9 111.3, 112.3, 120.9,131.1, 134.0, 147.7 125.0, 131.2, 136.4 (4-C, 2,6-CH, 3,5-CH, 1-C)(6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C) (5-C, 4-C, 2-CH) 13.02 13.2 121.8,128.0, 130.4, 130.7, 131.2, 131.3 110.4, 111.2, 119.7, 131.2, 134.0,149.5 126.0, 134.5, 137.9 (3-C, 6-CH, 4-CH, 2-CH, 5-CH, 1-C) (6-CH,2-CH, 4-CH, 5-CH, 3-C, 1-C) (5-C, 4-C, 2-CH) 13.03 14.2 127.5, 127.6,128.4, 130.5, 130.9, 134.6 110.5, 111.2, 119.7, 131.3, 134.1, 149.5126.1, 133.3, 137.9 (6-CH, 4-CH, 5-CH, 3-CH, 1-C, 3-C) (6-CH, 2-CH,4-CH, 5-CH, 3-C, 1-C) (5-C, 4-C, 2-CH) 13.04 19.4, 22.3, 23.1, 24.2110.9, 111.7, 119.9, 131.3, 134.1, 149.9 125.6, 134.8, 135.7 (7-CH₂,4-CH₂, 5-CH₂, 6-CH₂) (6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C) (5-C, 4-C, 2-CH)13.05 14.3 127.5, 128.5, 129.0, 132.0 111.7, 119.9, 129.4, 148.4 127.8,133.4, 137.5 (4-CH, 2,6-CH, 3,5-CH, 1-C) (2,6-CH, 4-CH, 3,5-CH, 1-C)(5-C, 4-C, 2-CH) 13.06 13.1 7.3 112.1, 120.2, 129.5, 148.4 122.8, 131.5,135.6 (2,6-CH, 4-CH, 3,5-CH, 1-C) (5-C, 4-C, 2-CH) 13.07 13.2 7.2 110.8,111.4, 119.8, 131.3, 134.1, 149.9 122.6, 130.9, 135.5 (6-CH, 2-CH, 4-CH,5-CH, 3-C, 1-C) (5-C, 4-C, 2-CH) 13.08 13.2 7.3 21.3(3-Me) 122.8, 131.4,135.6 109.4, 112.6, 121.1, 129.4, 138.7, 148.4 (5-C, 4-C, 2-CH) (6-CH,2-CH, 4-CH, 5-CH, 3-C, 1-C) 13.09 14.22 127.5, 128.5, 129.1, 129.821.2(3-Me) 126.2, 133.3, 137.5 (4-CH, 2,6-CH, 3,5-CH, 1-C) 109.0, 112.3,120.8, 129.3, 138.7, 148.4 (5-C, 4-C, 2-CH) (6-CH, 2-CH, 4-CH, 5-CH,3-C, 1-C) 13.10 14.2 127.5, 128.4, 129.0, 133.5 113.1(d, J^(F)=7.6Hz,115.8(d, J^(F)=23Hz), 128.7, 137.4, 144.8 (4-CH, 2,6-CH, 3,5-CH, 1-C)154.2, 158.8(2,6-CH, 3,5-CH, 1-C, 4-C) (5-C, 4-C, 2-CH) 13.11 14.31(CH₃)127.5, 128.4, 129.2, 129.2 21.2(3-Me) 127.4, 129.3, 137.5 20.8(CH₂)4-CH, 2,6-CH, 3,5-CH, 1-C) 108.9, 112.2, 120.7, 129.3, 138.8, 148.4(5-C, 4-C, 2-CH) (6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C) 13.12 21.059.7(CH₃O), 158.9(CO) 110.8, 111.4, 119.8, 131.3, 134.1, 149.9 112.3,141.9, 146.4 (6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C) (5-C, 4-C, 2-CH) 13.1312.4 125.6, 126.7, 127.2, 127.4 19.3(3,5 Me), 126.0, 131.3, 135.6 4-CH,2,6-CH, 3,5-CH, 1-C) 107.8, 119.9, 136.6, 146.7 (5-C, 4-C, 2-CH)(2,6-CH, 4-CH, 3,5-C, 1-C) 13.14 14.2 127.5, 128.5, 129.0, 129.154.9(OMe) 127.8, 133.3, 137.5 4-CH, 2,6-CH, 3,5-CH, 1-C) 97.9, 104.4,105.2, 130.3, 149.8, 160.5 (5-C, 4-C, 2-CH) (2-CH, 6-CH, 4-CH, 5-CH,1-C, 3-C) 13.15 14.1 118.7(CN) 110.5, 111.3, 119.8, 131.2, 134.0, 149.3125.6, 135.0, 138.2 111.8, 129.9, 130.2, 131.2, 132.1, 133.6 (6-CH,2-CH, 4-CH, 5-CH, 3-C, 1-C) (5-C, 4-C, 2-CH) (3-C, 5-CH, 1-C, 4-CH,2-CH, 6-CH) 13.16 14.2 118.7(CN) 21.2(3-Me) 125.9, 134.7, 138.3 111.7,129.8, 130.5, 131.0, 132.1, 133.6 109.1, 112.4, 121.1, 129.3, 138.8,148.0 (5-C, 4-C, 2-CH) (3-C, 5-CH, 1-C, 4-CH, 2-CH, 6-CH) (6-CH, 2-CH,4-CH, 5-CH, 3-C, 1-C) 13.17 10.1 167.2(CONH₂) 111.5, 112.4, 120.4,131.2, 134.0, 147.3 124.9, 126.1, 146.9 128.9, 128.9, 130.2, 130.6,131.2, 133.5 (6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C) (5-C, 4-C, 2-CH) (1-C,4-CH, 2-CH, 5-CH, 3-C, 6-CH) 13.18 12.3 165.9(CONH₂) 21.3(3-Me) 124.9,126.4, 145.8 128.9, 128.9, 130.2, 130.6, 131.2, 133.5 108.2, 11.6,119.4, 129.3, 138.8, 148.0 (5-C, 4-C, 2-CH) (1-C, 4-CH, 2-CH, 5-CH, 3-C,6-CH) (6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C) 13.19 14.0 52.3(MeO), 166.0(CO)111.9, 111.3, 119.3, 131.0, 133.6, 149.0 126.7, 129.8, 138.7 127.2,128.7, 129.2, 129.6, 130.7, 133.6 (6-CH, 2-CH, 4-CH, 5-CH, 3-C, 1-C)(5-C,4-C, 2-CH) (1-C, 4-CH, 5-CH, 2-CH, 6-CH, 3-C) 13.20 14.0167.2(CO₂H), 110.5, 111.2, 119.7, 131.2, 134.0, 149.5 127.0, 129.7,138.5 128.5, 128.9, 129.0, 129.8, 131.3, 133.3 (6-CH, 2-CH, 4-CH, 5-CH,3-C, 1-C) (5-C, 4-C, 2-CH) (4-CH, 1-C, 5-CH, 2-CH, 3-C, 6-CH)

TABLE 2 Examples of N-aminoimidazoles (13) as prepared according to thegeneral procedure described in scheme 3.

R⁶ R¹ R⁵ 13.01 C₆H₅ CH₃ 3-ClC₆H₄ 13.02 3-BrC₆H₄ CH₃ 3-ClC₆H₄ 13.033-ClC₆H₄ CH₃ 3-ClC₆H₄ 13.04 —(CH₂)₄— 3-ClC₆H₄ 13.05 C₆H₅ CH₃ C₆H₅ 13.06CH₃ CH₃ C₆H₅ 13.07 CH₃ CH₃ 3-ClC₆H₄ 13.08 CH₃ CH₃ 3-CH₃C₆H₄ 13.09 C₆H₅CH₃ 3-CH₃C₆H₄ 13.10 C₆H₅ CH₃ 4-FC₆H₄ 13.11 C₆H₅ CH₃CH₂ 3-CH₃C₆H₄ 13.12CH₃OCO CH₃ 3-ClC₆H₄ 13.13 C₆H₅ CH₃ 3-CH₃-5-CH₃C₆H₃ 13.14 C₆H₅ CH₃3-CH₃OC₆H₄ 13.15 3-CNC₆H₄ CH₃ 3-ClC₆H₄ 13.16 3-CNC₆H₄ CH₃ 3-MeC₆H₄ 13.173-NH₂COC₆H₄ CH₃ 3-ClC₆H₄ 13.18 3-NH₂COC₆H₄ CH₃ 3-MeC₆H₄ 13.193-MeOCOC₆H₄ CH₃ 3-ClC₆H₄ 13.20 3-HOCOC₆H₄ CH₃ 3-ClC₆H₄

1. An N-aminoimidazole or N-aminoimidazolethione derivative, apharmaceutically acceptable salt, a tautomer, an isomer, an ester or aglycosylation product thereof said derivative being a compoundrepresented by the general formula (I):

wherein: m is zero or 1; n is zero or 1; R¹ is selected from hydrogen,methyl, ethyl, propyl or isopropyl; R² is selected from hydrogen and—SH; Q is selected from 1-naphtyl, 2-naphtyl, biphenyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, thienyl,carboxyl, aminocarbonyl, alkylamino-carbonyl, dialkylaminocarbonyl,phenylaminocarbonyl, alkyloxycarbonyl or phenyl; wherein alkyl is amethyl, ethyl, propyl or isopropyl and phenyl is a substituted orunsubstituted phenyl ring represented by the general formula (II)

wherein o is 1 or 2, and R³ is selected from H, F, Cl, Br, I, hydroxy,alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, carboxyl,aminocarbonyl, alkylaminocarbonyl, alkyloxycarbonyl, methyl, ethyl,propyl, isopropyl or C₁₋₃ haloalkyl wherein haloalkyl contains 1 to 4haloatoms and alkyl is selected from methyl, ethyl, propyl or isopropyl;L is selected from 1-naphtyl, 2-naphtyl, biphenyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, thienyl, or asubstituted or unsubstituted phenyl ring represented by the generalformula (III)

wherein p is 1 or 2, and R⁴ is selected from H, F, Cl, Br, I, hydroxy,alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, carboxyl,aminocarbonyl, alkylaminocarbonyl, alkyloxycarbonyl, methyl, ethyl,propyl, isopropyl or C₁₋₃ haloalkyl wherein haloalkyl contains 1 to 4haloatoms and alkyl is selected from methyl, ethyl, propyl or isopropyl;with the proviso that the compound (I) is not selected from1-(3-Chlorophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;1-(2-Chlorophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;1-(4-Chlorophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;1-(phenylamino)-2,3-Dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;1-(4-nitrophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;1-(4-methylphenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;1-(4-methyloxyphenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;1-(benzylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;4-Methyl-5-phenyl-1-phenylamino-1H-imidazole;4-Methyl-5-phenyl-1-(4-nitrophenyl)amino-1H-imidazole;4-Methyl-5-phenyl-1-(4-chlorophenyl)amino-1H-imidazole;4-Methyl-5-phenyl-1-(4-methylphenyl)amino-1H-imidazole or4-Methyl-5-phenyl-1-(4-methyloxyphenyl)amino-1H-imidazole.
 2. A compoundaccording to claim 1, wherein m and n equal zero; Q is a substituted orunsubstituted phenyl ring represented by the general formula (II)

wherein o is 1 or 2, and R³ is selected from H, F, Cl, Br, I, hydroxy,alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, carboxyl,aminocarbonyl, alkylaminocarbonyl, alkyloxycarbonyl, methyl, ethyl,propyl, isopropyl or C₁₋₃ haloalkyl wherein haloalkyl contains 1 to 4haloatoms and alkyl is selected from methyl, ethyl, propyl or isopropyl;and L is a substituted or unsubstituted phenyl ring represented by thegeneral formula (III)

wherein p is 1 or 2, and R⁴ is selected from H, F, Cl, Br, I, hydroxy,alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, carboxyl,aminocarbonyl, alkylaminocarbonyl, alkyloxycarbonyl, methyl, ethyl,propyl, isopropyl or C₁₋₃ haloalkyl wherein haloalkyl contains 1 to 4haloatoms and alkyl is selected from methyl, ethyl, propyl or isopropyl.3. A compound according to claim 1, being selected from the followinggroup consisting of:2,3-Dihydro-1-(4-fluorophenylamino)-4-methyl-5-phenyl-1H-imidazole-2-thione;5-(3-Bromophenyl)-1-(3-chlorophenylamino)-2,3-dihydro-4-methyl-1H-imidazole-2-thione;5-(4-Bromophenyl)-1-(3-chlorophenylamino)-2,3-dihydro-4-methyl-1H-imidazole-2-thione;5-(3-Chlorophenyl)-1-(3-chlorophenylamino)-2,3-dihydro-4-methyl-1H-imidazole-2-thione;5-(4-Chlorophenyl)-1-(3-chlorophenylamino)-2,3-dihydro-4-methyl-1H-imidazole-2-thione;2,3-Dihydro-1-(3-chlorophenylamino)-5-(4-methoxyphenyl)-4-methyl-1H-imidazole-2-thione;1-(3-Chlorophenylamino)-2,3-dihydro-5-methyl-4-phenyl-1H-imidazole-2-thione;2,3-Dihydro-1-(3,4-dimethylphenylamino)-4-methyl-5-Phenyl-1H-imidazole-2-thione;1-(3-Bromophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;1-(3-Chloro-4-methylphenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;1-(2,5-Dichlorophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;2,3-Dihydro-4-methyl-1-(3-nitrophenylamino)-5-phenyl-1H-imidazole-2-thione;2,3-Dihydro-1-(3-fluorophenylamino)-4-methY1-5-phenyl-1H-imidazole-2-thione;2,3-Dihydro-4-methyl-1-(3-methylphenylamino)-5-phenyl-1H-imidazole-2-thione;2,3-Dihydro-4-isopropyl-1-(3-methylphenylamino)-5-phenyl-1H-imidazole-2-thione;1-(3-Chlorophenylamino)-2,3-dihydro-4-ethyl-5-phenyl-1H-imidazole-2-thione;2,3-Dihydro-4-ethyl-1-(3-methylphenylamino)-5-phenyl-1H-imidazole-2-thione;1-(3-Chlorophenylamino)-2,3-dihydro-5-methoxycarbonyl-4-methyl-1H-imidazole-2-thione;1-(3-Chlorophenylamino)-2,3-dihydro-5-hydroxycarbonyl-4-methyl-1H-imidazole-2-thione;2,3-Dihydro-1-(3,5-dimethylphenylamino)-4-methY1-5-phenyl-1H-imidazole-2-thione;1-(3-Methoxyphenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;1-(3-Chlorphenylamino)-5-(3-cyanophenyl)-2,3-dihydro-4-methyl-1H-imidazole-2-thione;5-(3-Cyanophenyl)-2,3-dihydro-4-methyl-1-(3-methylphenylamino)-1H-imidazole-2-thione;1-(3-Chlorphenylamino)-2,3-dihydro-4-methyl-5-(3-methoxycarbonylphenyl)-1H-imidazole-2-thione;2,3-Dihydro-4-methyl-1-(3-methylphenylamino)-5-(3-methoxycarbonyiphenyl)-1H-imidazole-2-thione;1-(3-Chlorphenylamino)-2,3-dihydro-5-(3-hydroxycarbonylphenyl)-4-methyl-1H-imidazole-2-thione;2,3-Dihydro-5-(3-hydroxycarbonylphenyl)-4-methyl-1-(3-methylphenylamino)-1H-imidazole-2-thione;5-(3-Carboxylamidophenyl)-1-(3-chlorphenylamino)-2,3-dihydro-4-methyl-1H-imidazole-2-thione;1-(3-Chlorophenylamino)-4-methyl-5-phenyl-1H-imidazole;5-(3-Bromophenyl)-1-(3-chlorophenylamino)-4-methyl-1H-imidazole5-(3-Chlorophenyl)-1-(3-chlorophenylamino)-4-methyl-1H-imidazole;1-(3-Chlorophenylamino)-4,5-dimethyl-1H-imidazole;4-Methyl-1-(3-methylphenylamino)-5-phenyl-1H-imidazole;1-(4-Fluorophenylamino)-4-methyl-5-phenyl-1H-imidazole;4-Ethyl-1-(3-methylphenylamino)-5-phenyl-1H-imidazole;1-(3-Chlorphenylamino)-5-methoxycarbonyl-4-methyl-1H-imidazole;1-(3,5-Dimethylphenylamino)-4-methyl-5-phenyl-1H-imidazole;1-(3-Methoxyphenylamino)4-methyl-5-phenyl-1H-imidazole;1-(3-Chlorophenylamino)-5-(3-cyanophenyl)-4-methyl-1H-imidazole;5-(3-Cyanophenyl)-4-methyl-1-(3-methyiphenylamino)-1H-imidazole;5-(3-Carboxamidophenyl)-1-(3-chlorphenylamino)-4-methyl-1H-imidazole;5-(3-Carboxamidophenyl)-4-methyl-1-(3-methylphenylamino)-1H-imidazole;1-(3-Chlorphenylamino)-5-(3-methoxycarbonylphenyl)-4-methyl-1H-imidazole;1-(3-Chlorphenylamino)-5-(3-hydroxycarbonylphenyl)-4-methyl-1H-imidazole;a pharmaceutically acceptable addition salt, or an ester thereof.
 4. Aprocess for preparing an N-aminoimidazolethione or N-aminoimidazolederivative, a pharmaceutically acceptable salt, a tautomer, an isomer,an ester or a glycosylation product thereof, said derivative being acompound represented by the general formula (I):

wherein: m is zero or 1; n is zero or 1; R¹ is selected from hydrogen,methyl, ethyl, propyl or isopropyl; R² is selected from hydrogen and—SH; Q is selected from 1-naphtyl, 2-naphtyl, biphenyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, thienyl,carboxyl, aminocarbonyl, alkylamino-carbonyl, dialkylaminocarbonyl,phenylaminocarbonyl, alkyloxycarbonyl or phenyl; wherein alkyl is amethyl, ethyl, propyl or isopropyl and phenyl is a substituted orunsubstituted phenyl ring represented by the general formula (II)

wherein o is 1 or 2, and R³ is selected from H, F, Cl, Br, I, hydroxy,alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, carboxyl,aminocarbonyl, alkylaminocarbonyl, alkyloxycarbonyl, methyl, ethyl,propyl, isopropyl or C₁₋₃ haloalkyl wherein haloalkyl contains 1 to 4haloatoms and alkyl is selected from methyl, ethyl, propyl or isopropyl;L is selected from 1-naphtyl, 2-naphtyl, biphenyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, thienyl, or asubstituted or unsubstituted phenyl ring represented by the generalformula (III)

wherein p is 1 or 2, and R⁴ is selected from H, F, Cl, Br, I, hydroxy,alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, carboxyl,aminocarbonyl, alkylaminocarbonyl, alkyloxycarbonyl, methyl, ethyl,propyl, isopropyl or C₁₋₃ haloalkyl wherein haloalkyl contains 1 to 4haloatoms and alkyl is selected from methyl, ethyl, propyl or isopropyl;with the proviso that the compound (I) is not selected from the groupconsisting of1-(3-Chlorophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;1-(2-Chlorophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;1-(4-Chlorophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;1-(phenylamino)-2,3-Dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;1-(4-nitrophenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;1-(4-methylphenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;1-(4-methyloxyphenylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;1-(benzylamino)-2,3-dihydro-4-methyl-5-phenyl-1H-imidazole-2-thione;4-Methyl-5-phenyl-1-phenylamino-1H-imidazole;4-Methyl-5-phenyl-1-(4-nitrophenyl)amino-1H-imidazole;4-Methyl-5-phenyl-1-(4-chlorophenyl)amino-1H-imidazole;4-Methyl-5-phenyl-1-(4-methylphenyl)amino-1H-imidazole; and4-Methyl-5-phenyl-1-(4-methyloxyphenyl)amino-1H-imidazole, said processcomprising the steps of reacting an α-haloketone having the formulaQ-(CH₂)—CO—CHR₁X, wherein Q, R₁ and n are as defined in formula (I) andX is a halogen atom, first with an alkali thiocyanate and then with ahydrazine derivative having the formula L-(CH₂)_(m)—NHNH₂, therebyobtaining an N-aminoimidazolethione derivative having the formula (I)wherein R₂ is —SH, and further optionally comprising the oxidativereduction of the said N-aminoimidazolethione derivative for preparing aderivative having the formula (I) wherein R₂ is hydrogen.
 5. A processaccording to claim 4, further comprising reacting theN-aminoimidazolethione derivative having the formula (I) wherein R₂ is—SH with an alkylating or glycosylating agent.
 6. A pharmaceuticalcomposition comprising an N-aminoimidazole or N-aminoimidazolethionederivative, a pharmaceutically acceptable salt, a tautomer, an isomer,an ester or a glycosylation product thereof, said derivative being acompound represented by the general formula (I):

wherein: m is zero or 1; n is zero or 1; R¹ is selected from hydrogen,methyl, ethyl, propyl or isopropyl; R² selected from hydrogen or —SH; Qis selected from 1-naphtyl, 2-naphtyl, biphenyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, thienyl, carboxyl,aminocarbonyl, alkylamino-carbonyl, dialkylaminocarbonyl,phenylaminocarbonyl, alkyloxycarbonyl or phenyl; wherein alkyl is amethyl, ethyl, propyl or isopropyl and phenyl is a substituted orunsubstituted phenyl ring represented by the general formula (II);

wherein o is 1 or 2, and R³ is selected from H, F, Cl, Br, I, hydroxy,alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, carboxyl,aminocarbonyl, alkylaminocarbonyl, alkyloxycarbonyl, methyl, ethyl,propyl, isopropyl or C₁₋₃ haloalkyl wherein haloalkyl contains 1 to 4haloatoms and alkyl is selected from methyl, ethyl, propyl or isopropyl;and L is selected from 1-naphtyl, 2-naphtyl, biphenyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, thienyl, ora substituted or unsubstituted phenyl ring represented by the generalformula (III);

wherein p is 1 or 2, and R⁴ is selected from H, F, Cl, Br, I, hydroxy,alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, carboxyl,aminocarbonyl, alkylaminocarbonyl, alkyloxycarbonyl, methyl, ethyl,propyl, isopropyl or C₁₋₃ haloalkyl wherein haloalkyl contains 1 to 4haloatoms and alkyl is selected from methyl, ethyl, propyl or isopropyl,as an active ingredient in admixture with at least a pharmaceuticallyacceptable carrier.
 7. A pharmaceutical composition according to claim6, having antiviral activity.
 8. A pharmaceutical composition accordingto claim 6, having activity against HIV (Human Immunodeficiency Virus).9. A pharmaceutical composition according to claim 6, wherein the saidactive ingredient is an agent for inhibiting the proliferation ofhepatitis B virus, hepatitis C virus or flaviviruses.
 10. Apharmaceutical composition according to claim 6, comprising said activeingredient in a concentration range from about 0.1 to about 100% byweight.
 11. A pharmaceutical composition according to claim 6, in a formselected from the group consisting of powders, suspensions, solutions,sprays, emulsions, concentrates, granulates, dusts, aerosols, tablets,pellets, ointments and creams.
 12. A pharmaceutical compositionaccording to claim 6, further comprising one or more retroviral enzymeinhibitors in respective proportions such as to provide a synergisticeffect against a viral infection in a mammal, as a combined preparationfor simultaneous, separate or sequential use in retroviral infectiontherapy.
 13. A pharmaceutical composition according to claim 6, furthercomprising one or more retroviral enzyme inhibitors in respectiveproportions such as to provide a synergistic effect against a viralinfection in a mammal, as a combined preparation for simultaneous,separate or sequential use in retroviral infection therapy, wherein theretroviral enzyme inhibitor is selected from HIV integrase inhibitors,reverse transcriptase inhibitors, nucleoside reverse transcriptaseinhibitors, non-nucleoside reverse transcriptase inhibitors and HIVprotease inhibitors.
 14. A method of treatment of a viral infection in amammal, comprising administering to the mammal in need of such treatmenta therapeutically effective amount of an N-aminoimidazole orN-aminoimidazolethione derivative, a pharmaceutically acceptable salt, atautomer, an isomer, an ester or a glycosylation product thereof; saidderivative being a compound represented by the general formula (I):

wherein: m is zero or 1; n is zero or 1; R¹ is selected from hydrogen,methyl, ethyl, propyl or isopropyl; R² is selected from hydrogen and—SH; Q is selected from 1-naphtyl, 2-naphtyl, biphenyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, thienyl,carboxyl, aminocarbonyl, alkylamino-carbonyl, dialkylaminocarbonyl,phenylaminocarbonyl, alkyloxycarbonyl or phenyl; wherein alkyl is amethyl, ethyl, propyl or isopropyl and phenyl is a substituted orunsubstituted phenyl ring represented by the general formula II;

wherein o is 1 or 2, and R³ is selected from H, F, Cl, Br, I, hydroxy,alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, carboxyl,aminocarbonyl, alkylaminocarbonyl, alkyloxycarbonyl, methyl, ethyl,propyl, isopropyl or C₁₋₃ haloalkyl wherein haloalkyl contains 1 to 4haloatoms and alkyl is selected from methyl, ethyl, propyl or isopropyl;and L is selected from 1-naphtyl, 2-naphtyl, biphenyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, thienyl, ora substituted or unsubstituted phenyl ring represented by the generalformula III;

wherein p is 1 or 2, and R⁴ is selected from H, F, Cl, Br, I, hydroxy,alkyloxy, amino, alkylamino, dialkylamino, cyano, nitro, carboxyl,aminocarbonyl, alkylaminocarbonyl, alkyloxycarbonyl, methyl, ethyl,propyl, isopropyl or C₁₋₃ haloalkyl wherein haloalkyl contains 1 to 4haloatoms and alkyl is selected from methyl, ethyl, propyl or isopropyl,as an active ingredient.
 15. A method of treatment according to claim14, further comprising administering to the mammal one or moreretroviral enzyme inhibitors in respective proportions such as toprovide a synergistic effect against viral infection.
 16. A method oftreatment according to claim 14, wherein the therapeutically effectiveamount of compound (I) is a retroviral replication inhibiting amount.17. A method of treatment according to claim 14, further comprisingadministering to the mammal one or more retroviral enzyme inhibitors inrespective proportions such as to provide a synergistic effect againstviral infection, wherein the said retroviral enzyme inhibitor isselected from HIV integrase inhibitors, reverse transcriptaseinhibitors, nucleoside reverse transcriptase inhibitors, non-nucleosidereverse transcriptase inhibitors and HIV protease inhibitors.
 18. Amethod of treatment according to claim 14, further comprisingadministering to the mammal one or more retroviral enzyme inhibitors inrespective proportions such as to provide a synergistic effect againstviral infection, and wherein the compound of formula (I) and theretroviral enzyme inhibitor are administered simultaneously, separatelyor sequentially.